Back in June 2021, we shared an article on ‘The challenges of adult acne’ (see here) to provide an introduction to acne development and some of the common treatments.
Now, our long-running contributor Dr Barbara Brockway builds on this, bringing us the latest in acne treatment and management…
Acne prevalence and causes
Acne vulgaris is the most common skin complaint, with approximately 85% of people aged 12–24 years experiencing at least minor acne [1]. Despite the many acne treatments and products on offer, the incidence rate is increasing [2]. Bearing in mind that cosmetics claiming to ‘treat’ acne are considered to be medicinal or as drugs in many major markets, the global market for anti-acne cosmetics is large and growing. In 2020, the acne industry was valued at USD 3.47 billion, and is expected to grow at 9.1% (CAGR) over the next 5 years [3].
Regardless of the type of acne, the symptoms stem from infected or inflamed sebaceous glands. During a breakout, excess sebum, malfunctioning keratinization and multiplying bacteria result in oily, blocked hair follicles; a perfect environment for the different strains of Cutibacterium acne to flourish. Once established, C. acnes populations release significant amounts of degradative enzymes and pro-inflammatory mediators. For example, Interleukin 8 (IL-8) is released when mediators activate Toll-like receptor 2 (TLR2) receptors in cells within the follicle, triggering an innate immune system response, which recruits and guides neutrophils to the infection [4].
A recent paper by Neill et al. shows that, like Staphylococcus aureus, C. acnes secretions can trigger the transformation of two subsets of fibroblasts into adipogenic fibroblasts [5]. These adipocytes play an important role in pimple formation and produce yet more lipid, which unfortunately aids the growth of even more C. acnes [6]. However, these adipocytes also produce the antimicrobial peptide cathelicidin, which helps suppress the infection. Sebocytes, neutrophils and other cells within the infected pilosebaceous units also produce antimicrobial peptides (cathelicidin and β-defensins), which together work synergistically to try and quell the infection. These antimicrobials are part of the skin’s natural healing process and act as signals to increase cell turnover, so worsening the situation [7].
Many factors contribute to acne development, including genetics, environmental factors, lifestyle and poor nutrition. However, the role of hormones in initiating acne must take centre stage. Acne normally occurs at puberty and again later in the lives of women who suffer with menopausal acne. Acne breakouts are less common during the stages in life when sex hormones, and in particular androgen, are not playing a major role, such as in elderly people and in the very young. It is well documented that androgens increase cell turnover and sebum production. The hormonal changes that start at puberty are the likely root cause off acne in most susceptible people [8] (as opposed to the coincidentally increased consumption of chocolate by teenagers, which is a common misconception [9]). Another hormone associated with acne and increased sebum production is cortisol. Acne breakouts often occur when people are under stress or when their sleep–wake cycle is disrupted. Cortisol is released during stressful situations and plays a key role in our circadian rhythms. Stressful modern lifestyles, long-distance travel and late nights may be contributing to the growing number of acne sufferers [10] (see also a previous article on circadian rhythms here).
So why me and not others?
The way that skin reacts to hormones and to C. acnes proliferation depends on an individual’s genetics, gene expression and general health, meaning that some are more predisposed to acne development than others. Since C. acnes strains were first isolated from acne pustules by Paul Gerson Unna in the late 1890s, C. acnes has been demonized as the main cause of acne. Paradoxically however, C. acnes is a key member of the healthy skin microbiome, as it helps strengthen our skin’s natural defences by priming the immune system against itself and similar microbes. Also, the balance between C. acnes and Staphylococcus epidermidis influences skins inflammatory response. Changing the balance in favour of S. epidermidis could trigger the release of IL-6 and other inflammatory molecules [11]. C. acnes‘ slow cell cycle, ability to form biofilms and preference for living in oxygen-deficient environments makes it a stubborn inhabitant of crevasses and pores. The presence of C. acnes prevents more threatening anaerobic/facultative anaerobic microbes from taking hold. Abundance and distribution patterns of C. acnes relate to the availability of sebum and are controlled by the skin’s innate defences and by competition with neighbouring microbes especially S. epidermis. As mentioned in the previous ‘The challenge of adult acne‘ article, there are particularly virulent C. acnes strains (phylotype IA1) that produce higher amounts of pro-inflammatory metabolites. Worryingly, there are also a growing number of antibiotic-resistant C. acnes strains. These are the C. acnes strains where our treatments (and vilification) need to be directed.
Treating acne
The most successful anti-acne products are those that address several causes and are used regularly for at least 2−3 months. For many decades, benzoyl peroxide (BPO), which is classified as a ‘drug’ in Europe, has been used at up to 10% in anti-acne treatments. Interestingly, at very low (micromolar) levels, BPO is anti-inflammatory. In these tiny amounts, it prevents neutrophils from releasing reactive oxygen species in response to infection [12]. However, BPO is effective against acne because it is an oxidant that breaks down on skin to form benzoic acid and oxygen [13]. In addition, its weak peroxide group (−O−O−) readily splits to form reactive free radicals that, as well as destroying C. acnes, damage proteins and make them far more susceptible to enzyme hydrolysis [14]. BPO therefore addresses two causes of acne. First, by forming benzoic acid, which is a well-known antimicrobial that is especially effective at acidic pH, and molecular oxygen, which together control the proliferation of low-oxygen-loving C. acnes. Second, BPO’s free radicals oxidize keratin and proteinaceous cell debris, which blocks pores, facilitating its enzymatic digestion.
Unfortunately, although BPO use is demonstrably comedolytic, the free radicals that it generates are indiscriminate and cause general lipid peroxidation, which damages cells, impairs skin barrier function and results in peeling, dryness, stinging, redness, burning and increased sensitivity to the sun. These side effects should reduce if less BPO is applied, which is why it is often recommended to combine BPO use with antibiotics, erythromycin and clindamycin. Clindamycin interferes with protein synthesis in S. aureus, S. epidermidis and C. acnes, which are all key members of skin microbiome. It is easy to see, therefore, how clindamycin − while helping BPO to subdue C. acnes proliferation – will lead to the disruption of the microbiome and encourage and aid the establishment of any clindamycin-resistant bacteria [15]. BPO is also combined with salicylic acid or with adapalene (a synthetic retinoid) to enhance efficacy. These combinations are kinder to the microbiome. BPO alone or in a combination has shown efficacy in combating acne for many suffers, but people with sensitive skin and very dry skin must avoid BPO due to the severity of the side effects.
Topical retinoids (such as adapalene, tretinoin and tazarotene), alone or with antibiotics, are another commonly prescribed treatment for sufferers of mild acne [16]. They have comedolytic properties and promote differentiation of keratinocytes. People with more severe acne are often offered similar remedies but these are reinforced with broad-spectrum oral antibiotics (such as tetracyclines, doxycycline and minocycline) or with other treatments, such as azelaic acid (AzA). Retinol, retinal (also known as retinaldehyde), retinoic acid and several provitamin A carotenoids (most notably β-carotene) are amongst the group of molecules known as vitamin A. The cosmetic industry uses many esters and derivatives of vitamin A, that they describe as retinol. For example, retinyl acetate, retinyl linoleate, retinyl palmitate and retinyl propionate. Retinyl acetate is a naturally occurring fatty acid ester form of retinol. It and other molecules with retinol-like activities bind to and activate retinoid receptors, decreasing lipid synthesis from sebaceous glands, inducing cell differentiation, altering the growth of epidermal cells and decreasing cell proliferation. Retinol and many of these compounds convert to retinoic acid, which promotes enhanced cathelicidin expression, inhibits adipogenesis and suppresses acne-like lesion formation [5].
Many antibiotics, including those already mentioned plus minocycline, have the added advantage of also being anti-inflammatory. However, in the case of doxycycline, minocycline and also the combination of trimethoprim with sulfamethoxazole, they can also cause photosensitivity and hyperpigmentation. Sulfonamides (usually sodium sulfacetamide) are another class of topical antibacterial agents used to treat acne. These sulfa drugs are especially helpful for controlling bacterial infections that are resistant to other antibiotics and can be made more effective by combining with sulfur (a keratolytic agent) [17].
AzA, already mentioned as a booster for topical retinoids, is used at concentrations of up to 20%, twice a day for at least 6 months, to treat mild to moderate acne. It works by supressing excessive protease activity, inhibiting the formation of biofilms and acting as an effective anti-inflammatory. AzA kills bacteria, while significantly reducing sebum production [18]. It resets the keratinization process in the follicle; however, on the downside, AzA inhibits melanin synthesis so will lighten skin. It also can cause itching, burning and redness but these effects normally disappear with continued use.
As acne is strongly associated with hormones, some treatments inhibit the action of androgens. For example, women acne suffers are prescribed the combined oral contraceptive to modulate the effects of androgens on their sebaceous glands [19]. Spironolactone is an androgen receptor antagonist, which is also used successfully to decrease sebum production [20].
Popular cosmetic approaches include the use of witch hazel for its astringent and antiseptic properties, or cider vinegar to unclog pores and to remove dead skin cells. Simply encouraging exfoliation with lactic acid, urea and hydroxy acids, such as glycolic acid or salicylic acid, can help some acne sufferers. Outside of cosmetics, salicylic acid is combined with clindamycin to make it a more effective acne treatment. Natural cosmetic actives, such as honey, tea tree oil, green tea and aloe vera, along with emollients and soothing actives, are used to help to moisturize and reduce inflammation [21].
Three other important cosmetic actives − allantoin, sodium ascorbyl phosphate and niacinamide (vitamin B3) − are discussed in the previous ‘Challenge of adult acne’ article. The moisturizing and keratolytic properties of allantoin make it a very useful anti-blemish active. It increases skins smoothness by enhancing exfoliation and promoting cell proliferation [22]. Sodium ascorbyl phosphate has antioxidant and antimicrobial activities that help reduce acne inflammation [23]. Niacinamide (vitamin B3) reduces irritation and soothes. More specifically, niacinamide prevents C. acnes pro-inflammatory mediators from activating TLR2 receptors and therefore downregulates IL-8 expression, reducing inflammation [24]. Niacinamide also slows sebum secretion and strengthens the skin barrier by increasing ceramide production [25].
Topical hydrocortisone is not a conventional acne treatment, but it does help reduce inflammation. Studies show that combinations of 1% hydrocortisone with BPO are more effective against acne than BPO alone, and that the inflammatory effects of BPO are significantly reduced [26]. Unfortunately, the negative effects of hydrocortisone, which include impaired wound healing, decreased skin elasticity and reduced skin thickness, can worsen acne.
Finally, nutrition and lifestyle are important for clear skin. Hyperkeratosis is associated with diets deficient in vitamin A and may also be linked to diets low in vitamin B complex, vitamin C, vitamin E and essential fatty acids. Health supplements recommended to acne suffers include zinc salts, as zinc can reduce sebum and balance keratin and collagen production, while also stopping overproduction of keratinocytes and thus helping to prevent blocked hair follicles.
Conclusion and future treatment outlook
Since the 1930s, BPO has been the go-to drug for acne treatments, but its harsh side effects mean that many suffers need alternatives. Retinoids, antibiotics, anti-inflammatories and cosmetic soothing actives, exfoliants, hormone inhibitors, moisturizers and so on all have their place in anti-acne products (see ref. 27 for a full review of traditional acne treatments). However, 130 years after the discovery of C. acnes, acne remains an increasing problem, and most treatments today (expect oral therapy with retinoic acid) do not satisfy as they cure the symptoms more than the disease itself. So, it is safe to say that, so far, a universal panacea for acne has not been found. Could targeting C. acnes hold the key?
Millions of years of evolution and trillions of generations have made C. acnes a successful member of a healthy skin microbiome. It can become a problematic microbe when factors such as hormone changes lead to an increase in sebum. As not everyone develops acne, other factors such as the genetics responsible for an individual’s response to C. acnes must also play a crucial role. Intraspecies diversity and the presence or absence of more virulent C. acnes strains has also been shown to play a part, as each adult has a unique mix of C. acnes strains co-existing within the skin [28] (see here for a more detailed look at how different strains come into play). Poor diet and topical and ingested antibiotics can be particularly hard on our skin microbiome and allow both virulent and antimicrobial C. acnes to take hold.
Microbe-directed therapy is therefore a promising research avenue that may be able to address the core of the disease. As the previous ‘Challenge of adult acne’ article also concludes,re-establishing the population of beneficial C. acnes strains (probiotherapy) – for example, by using oral or topical probiotics – can restore balance and help prevent acne development [29]. An interesting point here is the role of human anatomy – skin pores, for instance, play a critical role in C. acnes ecology as they limit competition, with each individual pore dominated by a single strain. Understanding how host anatomy and physiology influence strain-level composition in this way is critical for the design of microbiome-based therapeutics. In this case, pore dynamics suggest that the ability of a probiotic strain to engraft on sebaceous skin will depend less on the probiotic strain’s competitive fitness and more on efficient removal or destabilization of the existing community prior to treatment, so therapeutic interventions involving pore-dwelling species should focus on removing resident populations over optimizing probiotic fitness [28].
Such approaches, combined with advances in DNA technology (such as use of CRISPR-based gene editing to remove antibiotic resistance), may hold the key to eradicating acne. Stay tuned!
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References
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