Focus on Acne - Anthony Chu, FRCP. Professor of Dermatology

Acne is the commonest dermatosis to affect man but is generally poorly treated. It has a major genetic component (1) and must be regarded as a chronic inflammatory disease. It can scar the skin and the psyche causing lack of self-esteem, mood swings, depression and suicidal ideation (2).

Acne has changed significantly over the last 5 decades. In the 1970s, it was considered a teenage disease and would naturally resolve in about 5 years. A population-based study in USA (3) has confirmed our clinical impression that acne is now persisting in a high percentage of patients and it is impossible to predict when resolution will occur. In this study the incidence of acne at the age of 30-40 years was 35% in women and 20% in men and in those over 50 years, 15% in women and 7% in men. One possible reason for this is increased stress in modern society with stress stimulating adrenal gland function and increasing androgen production.

To treat acne properly you need to understand the pathophysiology of the disease, which has 4 important steps (4). 1. Sebum production is abnormally high due to an end organ response to normal levels of androgens and the sebum is deficient in linoleic acid. 30% women have higher androgen levels are part of the polycystic ovary syndrome. 2. Hyperkeratosis at follicular ostium restricts oil flow onto the skin. This is the first morphological change with the formation of the microcomedone. 3. Follicular occlusion leads to pooling of oil in the follicle which stimulates proliferation of the anaerobic commensal bacterium, Propionibacterium acnes, recently renamed Cutibacterium acnes. 4. Inflammation is induced by T helper cells reactive to C acnes antigens (5) with ultimate pus formation. Acne is a primary inflammatory disease of the skin and not an infection and C acnes does not fulfil Kock’s postulates.

Treatment

The treatment of acne has not fundamentally changed over the last 4 decades. In Primary Healthcare, topical or oral antibiotics are the mainstay with the use of topical retinoids. Antibiotics target the inflammatory lesions of acne but have no effect on the non-inflammatory microcomedones and comedones and must always be used with agents that will target these.

Non-inflammatory lesions

The major treatment are the topical retinoids. Retinoids normalise keratinocyte growth and thus prevent follicular hyperkeratinisation. The topical retinoids now available in UK are tretinoin, as a 0.025% cream or in combination with 1% clindamycin (Treclin gel) or 4% erythromycin (Aknemycin plus lotion), and adapalene as a 1% cream or gel or in combination with 2.5% benzoyl peroxide (Epiduo gel). Studies have shown that the absorption of topical retinoids is minimal. Topical retinoids can cause local photosensitivity so should be used at night and washed off in the morning. They may cause local skin dryness and irritation but this is often due to overuse. Microcomedones cannot be seen with the naked eye so all affected areas should be treated, not just where spots are present.

Salicylic acid is a desmolytic agent breaking down bonds between keratinocytes. 2% preparations are available OTC and can help reduce follicular hyperkeratosis. Azelaic acid as a 20% cream (Skinoren) has some comedolytic effects but its main effect in acne is on the inflammatory lesions

Inflammatory lesions

Antibiotics

Antibiotics work partly by killing C acne but have significant anti-inflammatory activity and studies in my laboratory have shown that antibiotics work in suppressing inflammatory acne lesions even when C acnes are resistant to them (6). The most common oral antibiotics used in acne are oxytetracycline and erythromycin, which are possibly the worst antibiotics to use due to their bioavailability. Oxytetracycline has a half-life of 6-8 hours and is inhibited by fat or iron in the stomach. Erythromycin has a half life of about 2 hours and is inhibited by carbohydrate in the stomach. These antibiotics need to be taken at least four times a day, on an empty stomach and without eating for a further hour – almost an impossibility for most patients

The newer tetracyclines such as lymecycline and doxycycline and macrolides such as clarithromycin have much improved bioavailability and should be used in preference. In patients not fully responding to a tetracycline or macrolide, trimethoprim, 300mg bd is a good second line drug (7)

Topical antibiotics achieve a high local concentration in the skin with minimal systemic absorption and thus side effects. Few are currently available – 1% clindamycin lotion or gel, 1% clindamycin with 3 or 5% benzoyl peroxide (Duac gel) and 4% erythromycin with zinc (Zineryt lotion). Drug resistance in C acnes quickly develops to topical antibiotics but this may not affect their efficacy. The addition of benzoyl peroxide prevents drug resistance from developing.

Non antibiotic treatments

Benzoyl peroxide is an organic peroxide used commercially to bleach flour. Pace was the first to use a preparation of benzoyl peroxide in acne in 1965 (8) and since then it has remained a highly effective and safe treatment. It works by releasing oxygen into the follicle where it kills anaerobic C acne. No resistance can develop which makes it an important treatment particularly in combination with antibiotics. Benzoyl peroxide preparation are available at 2.5 and 5%. They can cause skin irritation and more rarely act as a sensitiser. They also bleach fabric and clothing.

Aknicare lotion is a little known but very useful prescription or OTC treatment of acne. It contains triethyl citrate and ethylinoleate. These are metabolised in the follicle by C acnes to citric acid and linoleic acid. Citric acid reduces the pH inhibiting C acnes growth. It restricts bacterial enzyme reduction of sebum triglycerides maintaining integrity of sebum, reducing availability of glycerol to the bacteria, further restricting growth and supressing free fatty acid mediated inflammation. Linoleic acid and citric acid suppress 5α-reductase and thus the activation of testosterone. Clinical studies have shown that it is very effective in suppressing inflammatory lesions and significantly reduces sebum production (9). Linoleic acid increases the concentration of this in sebum and thus suppresses follicular hyperkeratinisation. It is particularly useful in women who are trying to conceive or who are pregnant where topical retinoids are contraindicated.

4% nicatinamide gel has anti-inflammatory activity and suppresses inflammatory lesion of acne but probably less effective than benzoyl peroxide. It has no effect on non-inflammatory lesions. 20% azelaic acid has anti-inflammatory activity.

Alternative treatments

Systemic drugs

Oral contraceptive pills containing cyproterone acetate (Dianette) or drospirenone (Yasmin) are effective in acne by suppressing androgen activity in women. They should be reserved for women who have severe acne not responding to conventional treatment. Both have significant side effects and Dianette can cause an initial flare of acne. In both drugs, acne may flare when the drug is stopped. Dianette is only recommended for short term us.

Spironolactone is an aldosterone blocking diuretic which also acts as an androgen receptor antagonist and at 100-200mg/day is very effective in women with hormonal acne (10). 10% women develop changes in their menstrual cycle. 

Dapsone is a sulphone drug with a major effect on the function of polymorphonuclear leukocytes. Worldwide it is a treatment for leprosy and in dermatology is the treatment of choice for dermatitis herpetiformis and various pustular dermatoses. In nodulocystic acne it can be very effective in reducing inflammatory lesions at 50mg/day. Patients should be screened for G6PD deficiency.

Oral isotretinoin is the most powerful drug we have to treat acne. It is licenced for the treatment of severe acne, acne not responding to conventional treatment or where there is a risk of scarring. It is, however, overused and often offered to patients with mild or moderate acne. It is a vitamin A derivative and is thus teratogenic and a pregnancy prevention program is used. Symptomatic side effects are common: dry skin, dry lips, photosensitivity, myalgias, arthropathy, night blindness and an effect on mental concentration. Most are self-limiting when the drug is stopped but up to 10% patients have long term xerosis. Patients must be warned of very rare but serious side effects which are totally unpredictable. These include acne fulminans, severe idiosyncratic depression and suicide (11), erectile dysfunction in men and loss of libido in women (12), severe persistent xerosis and cheilitis and fatigue syndrome. These severe side effects do not resolve on cessation of the drug.

Light and Lasers

Red light at 660nm aids healing by stimulating cytokine production. Blue light at 415nm activates coproporphyrin in C acne which kills the bacteria. Studies have shown that a system of red and blue fluorescent tubes were as effective as treatment with 5% benzoyl peroxide over a 12-week treatment period (13). Since that time a number of LED systems using red and blue light have become commercially available but none have been subjected to randomised clinical trials for efficacy

The Regenlite laser (formerly the NLite laser) is a pulsed dye laser with a unique waveform (see figure 1). This gives the laser a unique medical effect on the skin by inducing high levels of transforming growth factor β (TGF β) (14). TGF β is a potent anti-inflammatory cytokine which can induce T regulator cells, which in the case of acne, can turn off the immunological response responsible for the inflammation. Clinical trials have shown high efficacy in treating inflammatory acne requiring a single treatment every 3 months (15).

Figure 1. Pulse wave of Regenlite laser compared to traditional pulsed dye laser

Salicylic acid peels : Studies using a 30% salicylic acid peel with triethyl citrate and ethyl linoleate (Enerpeel SA) showed that after one application, the stratum corneum was reduced by 70%  and microcomedones were reduced (16). A sequence of this peel is medically licensed for the treatment of comedogenic and inflammatory acne and as an adjunct to conventional treatment, has an obvious place. 

Common Pitfalls

Why has treatment not worked? Most studies have identified user failure as the most common cause – patients not using treatment properly or not at all. The more complex the regime the less likely the patient will comply. Regular use of the topical retinoid, however, is essential in all acne patients.

If patients have very oily skin, oral antibiotics may be passed to the surface before they are able to work. In such cases, studies have shown that an increase in the antibiotic dosage can be effective (17)

Another common cause of treatment failure is the presence of macrocomedones. These are deep blockages in the follicle which may be invisible until the skin is stretched and the <1mm bump can be seen. These do not respond to topical retinoids and are the cause of recurrent deep inflammatory spots, particularly around the jawline in women. They are a contraindication to oral isotretinoin as they can cause a major flare of inflammatory spots at the start of treatment. The only way to deal with them is to lightly cauterise the skin above them using a hyfrecator

References

1. Bataille V, Snieder H, MacGregor AJ, Sasieni P, Spector TD. The influence of genetics and environmental factors in the pathogenesis of acne: a twin study of acne in women. J Invest Dermatol. 2002;119:1317-22.
2. Habeshian KA, Cohen BA. Current issues in treatment of acne vulgaris. Paediatrics 2020; 145:S225-S230
3. Collier CN; Harper JC; Cantrell WC et al. The prevalence of acne in adults 20 years and older. J Am Acad Dermatol. 2008; 58:56-9
4. Kircik LHJ. Advances in the understanding of the pathogenesis of inflammatory acne, Drugs Dermatol. 2016; 15:7S-10S
5. Mouser PE, Baker BS, Seaton ED, Chu AC. Propionibacterium acnes-reactive T helper-1 cells in the skin of patients with acne vulgaris. J Invest Dermatol. 2003;121(5):1226-8
6. Incidence and clinical importance of antibiotic drug resistance in Propionibacterium acnes in patients with acne on antibiotic therapy. Charikida A, Morris J, Chu A. Presented at 2nd Chinese-Anglo Dermatology Conference, Guangzhou, China 2004
7. Bottomley WW, Cunliffe. Oral trimethoprim as a third line antibiotic in the management of acne vulgaris. Dermatology. 1993;187:193-6
8. Pace WE. A benzoyl peroxide-sulfur cream for acne vulgaris. Can Med Assoc J. 1965; 93:252-234
9. Charikida A, Charikida M, Chu AC. Double blind randomised placebo controlled study of a lotion containing triethyl citrate and ethyl linoleate in the treatment of acne vulgaris. Br J Dermatol 2007; 157: 569-74.
10. Chamy JW, Choi JK, James WD. Spironolactone for treatment of acne in women, a retrospective study of 110 patients. Int J Womens Dermatol. 2017; 3:111-115
11. Hull PR, D’Arcy. Isotretinoin use and subsequent depression and suicide: presenting the evidence. Am J Clin Dermatol. 2003;4:493-505
12. Hogan C, Le Noury J, Healy D et al. One hundred and twenty cases of enduring sexual dysfunction following treatment. Int J Risk Saf Med. 2014;26:109-16.
13. Papageorgiou P. Katsambas A, Chu A. Phototherapy with blue (415nm) and red (660) light in the treatment of acne vulgaris. Br J Dermatol. 2000;142:973-8.
14. Seaton ED, Mouser PE, Charikida A, Alam S, Seldon PM, Chu AC. Investigation of the mechanism of action of nonablative pulsed-dye laser therapy in photorejuvination and inflammatory acne vulgaris. Br J Dermatol 2006; 155: 748-55
15. Seaton ED, Charakida A, Mouser P, Grace I, Clement RM, Chu AC. Pulsed-dye laser treatment for inflammatory acne vulgaris: randomised controlled trial. Lancet. 2003; 362:1347-52
16. Raone B, Veraldi S, Raboni R et al. Salicylic acid peel incorporating triethyl citrate and ethyl linoleate in the treatment of moderate acne: a new therapeutic approach, Dermatol Surg. 2013;39:1243-51
17. Eady EA, Cove JH, Holland KT et al. Recalcitrant acne vulgaris. Clinical, biochemical and microbiological investigation of patients not responding to antibiotic treatment. Br J Dermatol. 1988;118:415-23

Content provided by Anthony Chu, FRCP. Professor of Dermatology.