Messages From Molecules: Deciphering the Code

June 2013 | Volume 12 | Issue 6 | Supplement | s70 | Copyright © 2013

Jonathan S. Weiss MD

Gwinnett Dermatology, Snellville, GA

Abstract

Acne therapy should be based on pathogenesis. Current mainstays of therapy include topical retinoids, antibiotics, and benzoyl peroxide. Newer research has shown that inflammation may precede comedo formation. Gene array analysis of acne lesions has elucidated newer inflammatory mediators that may become future targets for therapeutic development.

J Drugs Dermatol. 2013;12(suppl 6):s70-s72.

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INTRODUCTION

Acne, like any other disease, demands that the practitioner understand its pathogenesis to implement treatment in a logical, medically sound manner. Gone are the days of the mid-20th century when dermatologists had limited products that were felt to be effective in the treatment of acne, and about which little was known of their exact mechanism of action, let alone how little was known about the underlying biochemical and pathologic basis of the disease. Combination therapy is the gold standard for acne therapy, as dermatologists employ topical agents, systemic agents, or both in any individual patient. The challenge that we face is to use acne medications in the most rational manner possible to treat the condition effectively. Further, as we research the next generation of acne therapies, a thorough understanding of the biochemical and molecular basis of the pathogenesis of acne will allow researchers and clinicians to more effectively develop and implement therapies.

Pathogenesis

The main pathogenic factors in acne remain (1) hyperkeratinization, (2) inflammation, (3) bacterial proliferation (Propionibacterium acnes), and (4) overproduction of sebum under hormonal influences. Concepts on the relative importance of each of these factors in the pathogenesis of acne are evolving. Throughout much of the past 50 years, it was accepted that the microcomedo was the basis of all subsequent acne lesions (Figure 1). A clinically undetectable, microscopic keratinous plug occludes the hair follicle, leading to follicular dilation, which ultimately results in the clinical lesion recognized as the comedo. If the orifice of the comedo is open, the keratinous plug turns black, resulting in a blackhead, or open comedo. If the orifice remains closed, the earliest clinical lesion is a closed comedo, or whitehead. Behind the keratinous plug, bacteria can proliferate, leading to recruitment of neutrophils and resulting in inflammation that is recognized clinically as acneiform papules and pustules.

More current research has led to the discovery that inflammation precedes comedo formation,1 so it is possible that the comedo is actually an inflammatory lesion, at least in some (if not all) patients (Figure 2). Jeremy et al demonstrated in an immunohistochemical study that inflammatory markers preceded the formation of microcomedones in acne patients.1 Furthermore, some studies of oral antibiotics used as single agents to treat acne demonstrated a reduction in the number of comedones, suggesting that anti-inflammatory activity itself can help reduce these lesions.2 Propionibacterium acnes, the bacterium that drives acne, remains a viable target for acne therapy.2 However, P acnes has begun to develop resistance to many of the antimicrobial agents that were formerly effective in treating acne. Furthermore, many of the antibiotics used to treat acne, namely doxycycline and trimethoprim/sulfamethoxazole, are important in the fight against methicillin-resistant Staphylococcus aureus; so reducing their use in the treatment of acne garners importance. As we move forward, finding and using agents other than antibiotics to reduce and/or ameliorate the proinflammatory effects of P acnes should become a focus of research.

While hormonal factors that influence sebum production play a role in driving acne pathogenesis, they appear to affect some patients more than others, especially women. Therapeutic agents that address hormonal contributions to acne include spironolactone and oral contraceptives. Many women respond well to these agents when used as adjuvant therapy. Hormonal targets will not be further discussed in this paper.

Therapeutic Targets: Molecules Matter

In considering therapeutic targets, 3 categories of molecules are central to the importance of current and future acne therapy: (1) inflammatory mediators, (2) cellular targets, and (3) pharmacologic compounds.

With the revelation that inflammation may precede hyperkeratinization and comedo formation, targeting inflammatory mediators should become a major focus of acne therapy research. Trivedi et al performed gene array analysis of acne lesions and found upregulation of multiple genes associated with inflammation and tissue remodeling.3 Upregulated genes included matrix metalloproteinases (MMPs) 1 and 3, interleukins (ILs) 8 and 1, β-defensin 4, serine proteases, L-selectin (lymphocyte adhesion molecule 1), chemokine receptor 1, tenascin C, and CD163 antigen.3 The degree of upregulation and the roles of these molecules in inflammation and/or tissue remodeling are noted in Table 1.3 In reviewing the molecules that are upregulated in acne lesions, it becomes apparent that therapies that target these molecules may help to reduce both inflammation and processes that lead to scarring, an issue that is poorly addressed by today’s therapeutics.

Cellular targets for the reduction of inflammation in acne include leukocyte migration, Toll-like receptor 2 on neutrophils,

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