Re-evaluating Treatment Targets in Acne Vulgaris: Adapting to a New Understanding of Pathophysiology

Two primary factors are changing current approaches to the management of acne vulgaris (AV): the continuously evolving role of Propionibacterium acnes in the pathophysiology of AV and emerging evidence of an inflammatory basis for AV. The developing concepts emphasize that acne is primarily an inflammatory disease. Recent research has confirmed that inflammation is the hallmark of all acne lesions, from the microcomedo to so-called “noninflammatory” lesions (open and closed comedones), to inflammatory lesions (papules, pustules, nodules, and "cysts"), to “postinflammatory” erythema and hyperpigmentation and scarring.

The pathophysiology of acne and associated scarring were elucidated with reports of marked elevations in inflammatory cytokine gene transcripts in active acne lesions, including tumor necrosis factor (TNF)-α and interleukin (IL)-1β, leading to an amplification of nuclear factor (NF)-kB signaling pathways. There were also significant increases in IL-8 and IL-10 and elevated activator protein (AP)-1 in acne lesions. This leads to elevated matrix metalloproteinases, which degrade collagen up to 2.5 fold compared with normal skin. Moreover, this inflammatory process was localized to the pilosebaceous unit.¹

Given these findings, clinicians are re-evaluating their therapeutic targets in the pathogenesis of AV and exploring optimal regimens that reduce inflammation without contributing to antibiotic resistance.

There was no doubt that inflammation played an important role in the development of inflammatory lesions, such as papules and pustules, or that P. acnes played a role leading to secondary inflammatory processes in those stages of acne development. Recent research has elucidated the role of inflammation in the pathogenesis of acne and, more precisely, the contribution of P. acnes to drive inflammation.^1-9 It was already well established that acne is not an infectious process.² P. acnes is now shown to drive the inflammation of AV via various different pathways throughout the course of the disease process, one of the most important is via the activation of innate immunity.³ P. acnes is thought to instigate an inflammatory cytokine response via activation of toll-like receptor (TLR)-2,³ which triggers a proinflammatory cytokine pattern.^1-7

However, we are now discovering that subclinical inflammation is present at the onset of disease and it is not only driven by P. acnes. Studies by Jeremy et al and others have shed light on the concept of early preclinical inflammation in acne⁸ that typically persists throughout the acne lesion life cycle.^6-7 They have documented a prelesional folliculocentric inflammatory phase of acne, evidenced by markedly increased numbers of CD4+ T lymphocytes; numbers of macrophages; upregulated expression of perifollicular IL-1; and upregulation of epidermal expression of α-integrins. These mediators are elevated in both normal skin and early papules of subjects with acne compared with normal skin of subjects without acne. Additionally, in subjects with acne, lesions had increased inflammatory mediators relative to uninvolved skin. Those mediators are also part of the immune system activation. More importantly, they were able to show that prelesional inflammation preceded follicular hyperkeratinization and the presence of microcomedones.⁸ These findings suggest that the so-called