Systemic antibiotics
In moderate-to-severe acne, and in cases of back, shoulder and chest involvement, and where topical therapies have failed, a course of systemic antibiotics should be considered. Antibiotics have both antimicrobial and anti-inflammatory effects: agents commonly used include tetracyclines (tetracycline, oxytetracycline, lymecycline, doxycycline, minocycline), macrolides (erythromycin, clarithromycin), and trimethoprim. In addition to the anti-inflammatory effects of tetracyclines, they act through inhibition of MMPs, inhibition of neutrophil chemotaxis, down-regulation of pro‑inflammatory cytokines, antioxidant properties, and inhibition of cell proliferation and angiogenesis1,3.
Current evidence shows comparable efficacy of doxycycline, lymecycline, minocycline, and tetracycline against inflammatory lesions3. As there remains little conclusive evidence as to the superiority of any one antibiotic over others, choice of antibiotic is governed by patient preference, side-effect profile, likelihood of concordance and cost. Response to regular use of an oral antibiotic should be gauged at least 8 weeks after instigation, before considering switching to an alternative agent. Typical treatment duration is 3–6 months, but longer durations are justified in selected cases. The burgeoning problem of increasing community antibiotic resistance may be avoided by concurrent use of topical benzoyl peroxide with systemic antibiotics and avoidance of concomitant topical antibiotic application, in addition to avoidance of antibiotic switching when an antibiotic has previously been efficacious.
Isotretinoin
In cases of severe acne, and where two or more protracted courses of systemic antibiotics together with other therapies have failed to control the disease, systemic isotretinoin can be considered by a dermatologist. It should also be considered in cases of severe cystic acne, acne fulminans, and where there is evidence of scarring. Isotretinoin, a retinoid, is hugely effective in the treatment of acne, being the only therapy to effectively target all four aforementioned underlying mechanisms. In addition, it has effects on MMPs, normalising their expression pattern and that of their inhibitors; a vital mechanism in arresting the scarring process largely attributed to the action of MMPs. Its use is limited by side‑effects, for which the patient must be counselled and documented consent obtained prior to commencement of treatment, which requires regular monitoring throughout the course of treatment12.
Foremost among these is teratogenicity, with babies born to mothers who have taken isotretinoin at any time during their pregnancy being at high risk of craniofacial, nervous system and cardiovascular abnormalities. The British Association of Dermatologists’ Guidelines recommend that all women of child-bearing potential should be counselled of this risk and receive the patient information leaflet of the brand they are due to take. Two methods of contraception are advised 1 month prior to initiation, throughout treatment and 1 month after cessation of isotretinoin therapy13.
Dosage usually starts at 0.5 mg/kg body weight and is increased as tolerated to 1 mg/kg body weight. The cumulative dose aimed for is 120–150 mg/kg body weight, typically over a 20-week time span. Following such a course of systemic isotretinoin, 40% of patients feel that their acne has fully resolved, 40% require less intensive treatment, and 20% may require a further course of isotretinoin. In cases of severe inflammation, a short course of oral steroids can be considered concurrently with isotretinoin.
What’s new?
Our understanding of diseases evolves with time as new evidence emerges and old notions are challenged. This has similarly been the case in acne vulgaris with some interesting developments published over the last few years.
The traditional view of acne lesion progression from the microcomedone to either a clinically visible comodone or an inflammatory lesion has been challenged by emerging evidence, which has shown the presence of subclinical inflammation preceding the microcomedone formation. Immunohistochemical studies identified significant inflammation around clinically-normal follicles of uninvolved skin from acne patients prior to follicular hyperkeratinisation. These included CD4 T-cells, up-regulation of IL-1, and integrin expression. Another study demonstrated the presence of inflammatory cell infiltrates in acne scarring in the absence of visible clinical inflammatory lesions. P. acnes has been shown to promote inflammation in its non‑viable state through up-regulation of TLR-2. These studies highlighted the persistence of inflammation throughout the acne life cycle, a finding that could have implications on early and continuous treatment of the inflammatory component. There is increasing evidence showing up-regulation of multiple genes associated with inflammation and tissue modelling, which include MMPs 1 and 3, IL-1 and IL-8, β-defensin 4, L-selectin, tenascin C, and CD163 antigen14.
Increasing evidence has shown that the sebaceous gland is modulated by neuropeptides and acts as an independent neuroendocrine organ. Both the expression of melanocortins (MCs) and corticotrophin-releasing hormone (CRH) play a functional role in sebaceous gland activity with the CRH-pathway likely to explain the role of stress (leads to an increase in CRH levels) in acne.
The role of diet in the pathogenesis of acne has always been controversial. Some recent studies have demonstrated a possible link with certain food items that could play a role in acne, particularly through the mediation of IGF. High-glycaemic index diet has been shown to stimulate the IGF-1 receptors leading to sebogenesis and follicular hyperkeratinisation. IGF-1 has also been shown to stimulate adrenal and gonadal androgen synthesis, androgen receptor signal transduction, and lipogenesis. Interestingly chocolate and skimmed milk (the latter possibly partly owing to the presence of a precursor of 5α-DHT in milk called 5α-pregnanedione in addition to an increase in IGF-1) have also been shown to worsen acne, while the consumption of fish was associated with a protective effect. A possible role of dietary effect may be the result of an increase in androgen levels, an observation particularly with whey-containing protein supplements that have mild androgenic effects. The roles of omega-3 fatty acids and zinc have yet to be proven.
The role of the innate immune system in acne was clearly demonstrated through the up-regulation of TLR-2 by P. acnes. TLRs are pattern recognition receptors that elicit an innate immune response through activation of the transcription factors, NF-κB and AP-1. Both modulate intracellular signalling cascades leading to up-regulation pro-inflammatory cytokines (particularly TNF-α, IL-1 and -8, and MMP). Topical retinoids have been shown to down-regulate TLRs, a mechanism that explains its high efficacy in the treatment of acne vulgaris. P. acnes has also been shown to elicit cellular responses via the protease-activated receptor-1 (PAR-2) with down-stream signalling, which mediates inflammation14,15. These studies have elaborated on the role of protease signalling in acne triggered by P. acnes.
The concept of biofilms in dermatology has gained a lot of attention recently, with our improved understanding of its role in skin diseases and management. Biofilms are diverse communities of microorganisms embedded within a self-produced matrix of extracellular polymeric substance, which are firmly attached to biotic or abiotic surfaces. They act as protective barriers against antimicrobial agents. With the relative recent elucidation of the P. acnes strain KPA171202, genome sequencing has demonstrated the presence of genes involved in the production of EPS and QS molecules; structures that are vital in the formation of the glycocalyx ‘adhesive glue’ of the P. acnes biofilms. This ‘adhesive glue’ serves to adhere the keratinocytes to the infundibular epithelium and the P. acnes to the sebaceous glands leading to comedogenesis and relative poor response to antimicrobial therapy16.
The future?
Medicine evolves and is ever-changing with new evidence emerging and old accepted theories challenged. Acne remains a challenge, but we have seen a great amount of advances over the last few years. Dermatologists and scientists are continuing to work on a better understanding of the pathogenesis and treatment. The area of biofilms is interesting with possible future therapies targeting the glycocalyx structures allowing for better response to therapy. The role of PPAR receptors on sebogenesis is also of interest and we may not be far from anti-PPAR therapies for acne. This would similarly be the case with anti-MCR or CRH receptor drugs.
Finally, the role of diet in acne is becoming a bit clearer, and in future this may lead to a change of attitude toward the advice we give to acne sufferers.
Conclusions
Acne vulgaris remains one of the most common dermatological pathologies, with high prevalence and profound psychosocial consequences. While recognised to have a familial propensity, its aetiology is multifactorial and remains largely unknown. Early recognition and active treatment avoids post-inflammatory scarring and hyperpigmentation, which remain difficult to treat. Evolving evidence is emerging on the role of diet and subclinical prelesional inflammation (occurring prior to or concurrent with follicular hyperkeratinisation), along with the role of P. acnes initiating an inflammatory response through TLR-2, all of which may have future implications on therapy. Further large randomised controlled trials comparing different topical and systemic agents are required to devise the optimal initial treatment algorithm, taking into account the burgeoning problem of antibiotic resistance.
