Acne

• Disease Site
• Incidence
• Predisposing Factors
• Macroscopic Features
• Microscopic Features
• Natural History
• Clinical History
• Clinical Examination
• Specific Investigations
• Prognosis
• Treatment Overview
• References

Disease Site

Acne is one of the commonest inflammatory skin disorders, with lesions developing from sebaceous glands associated with hair follicles located predominantly on the face, neck, chest, back and anogenital areas. Typically occurring in the middle to late adolescence years, the process is presumably secondary to hormonal changes and alterations in hair follicle maturation. The condition is characterised by non-inflammatory follicular papules or comedones (blackheads and whiteheads) and by inflammatory papules, pustules, and nodules in its more severe forms.
The following is a picture of an adolescent who has severe widespread acne affecting the face:

Children

In some cases, acne and acneiform lesions can also occur in infants. A young infant may demonstrate an acne eruption around the nose or cheeks. The cause of infantile acne is unknown. It has been thought to be hormonal in origin, involving adrenal androgens such as dehydroepiandrosterone. Occasionally excessive testosterone, luteinizing hormone and follicle stimulating hormone have been found.
In most infants with acne, no investigations are necessary and the eruption typically clears in a few weeks, without treatment. Infantile acne usually appears as rash with comedones and papules on the face.
The following is a picture of a young infant with acne:

The sebaceous gland contains holocrine cells, which secrete fatty acids, triglycerides, wax esters and sterols known as sebum.
The main changes in acne include:¹

• Increased sebum production;
• Thickening of the keratin lining of the sebaceous duct;
• Increase in propionobacterium acne bacteria in the duct;
• Increase in free fatty acids;
• Inflammation around the sebaceous gland.

Incidence

Acne is a common skin disease that affects 85-100% of people at some time during their lives.⁴ Acne is so prevalent it is almost considered a ‘normal’ process of development.³ Acne is often a self-limiting disorder that primarily affects teenagers and young adults. It is one of the most common reasons for young patients to consult a general practitioner.

Adolescents

In Australia, it is estimated that 95-100% of 16-17-year-old boys and 83-85% of 16-17-year-old girls are affected by acne.³ The most severe phase occurs between 14 and 17 years of age for girls, and 16 and 19 years of age for boys.³ The prevalence steadily declines after adolescence.

Adults

Approximately 10-20% of adults may continue to experience some form of the disorder.⁷ It is estimated that 1% of men and 5% of women still suffer from acne lesions at the age of 40.³

Predisposing Factors

Four key factors are thought to be responsible for the development of an acne lesion. These factors include follicular epidermal hyperproliferation with subsequent plugging of the follicle; excess sebum; the presence and activity of the skin bacteria Propionibacterium acnes; and inflammation.^1,4,6

Follicular epidermal hyperproliferation⁴

This is the initial recognised event in the development of acne. The exact underlying cause of hyperproliferation is not known. There have been various hypotheses regarding the reason why follicular epithelium is hyperproliferative in individuals with acne.
Firstly, androgen hormones have been implicated as the initial trigger. Comedones begin to appear around adrenarche in persons with acne. The degree of comedonal acne correlates with circulating levels of the adrenal androgen dehydroepiandrosterone sulfate (DHEA-S) in pre-pubertal girls.
Changes in lipid composition have also been implicated in the development of acne. People who are prone to acne have demonstrated increased sebum production and oily skin. Excess amounts of sebum can dilute the normal lipids present and alter the composition of the normal epidermal lipids.
Inflammation is another factor hypothesised to play a role in comedone formation. Interleukin-1 alpha is a pro-inflammatory cytokine which has been used in tissue models to induce follicular epidermal hyperproliferation and comedone formation.

Excess sebum

Regulation of sebum production and excretion involves a number of different hormones and mediators. Androgen hormones play a predominant role in promoting sebum production and release. Most people with acne have normal circulating levels of androgen hormones – it is hypothesised that there is an end-organ hyper-responsiveness to androgen hormones.⁴

Propionibacterium acnes

Propionobacterium acnes is an organism which flourishes in many acne lesions. It promotes inflammation through a variety of mechanisms. Individual hypersensitivity levels to Propionibacterium acnes may explain why some individuals develop inflammatory acne while others do not.

Inflammation

There is stimulation of inflammation through production of pro-inflammatory mediators, including IL-12, IL-8, and tumour necrosis factor. Inflammation can be a primary or secondary phenomenon. Evidence has primarily demonstrated a secondary inflammatory response to Propionibacterium acnes, however interleukin-1 alpha expression has been identified in the microcomedone, and may also play a role in the development of acne.⁴

Other factors

Physical factors

Apart from these primary processes that are necessary for the development of acne, exogenous factors can alter the expression of acne. Friction and trauma may rupture pre-existing microcomedones and induce inflammatory acne lesions. This is seen with headbands rubbing on the skin, or with the chin straps of helmets. Application of comedogenic topical agents in cosmetics or chronic topical exposure to certain comedogenic industrial compounds may elicit or aggravate acne.

Medications

Medications such as glucocorticoids (topically or administered in high doses systemically), lithium, azathioprine, isoniazid, halogens, cyclosporin, phenytoin, and phenobarbitone may also produce acneiform eruptions, or aggravate pre-existing acne.²

Hormones

In rarer cases, there may be an excessive amount of androgens due to disorders such as polycystic ovarian syndrome (PCOS), also known as Stein-Leventhal syndrome. This is a disorder of young women and is associated with oligomenorrhea, infertility, hirsutism, obesity, persistent anovulation and fibrotic cystic ovaries. Patients exhibit excessive production of androgens, increased conversion of androgen to oestrogen, and inappropriate gonadotrophin production by the pituitary.⁵

Macroscopic Features

The clinical hallmark lesion in acne is the comedone, which may be closed (whitehead) or open (blackhead). Closed comedones have the appearance of small white raised papules, and are the precursors of inflammatory lesions in acne. The contents of closed comedones are not easily expressible. Open comedones have a large widened follicular orifice and are filled with easily expressible, oxidised, darkened, oily debris. Comedones are usually accompanied by inflammatory lesions, including papules, pustules, or nodules.²
In early adolescence, the lesions are usually mildly inflamed or non-inflammatory comedones, located on the forehead. Subsequent inflammatory lesions may develop on the cheeks, nose, chin and, less commonly, the chest and back. Usually, the disease is mild and does not scar, but in some patients, there may be large inflammatory cysts which can lead to significant scarring.²

Microscopic Features

Histologically, comedones are composed of expanding masses of lipid and keratin at the mid-portion of hair follicles, with follicular dilation and epithelial and sebaceous gland atrophy. There is usually a variable lymphohistiocytic infiltrate and, in cases of rupture, there is extensive acute and chronic inflammation, occasionally with ensuing scar formation.⁵

Natural History

Acne tends to resolve in the third decade of life as androgen levels decline, although it may persist into, or develop for the first time, in adulthood. Post-adolescent acne predominantly affects women (12% of women and 5% of men at age 25), in contrast to adolescent acne, which predominantly affects males. Premenstrual flares of acne appear to be more common in older women.^6,7

Clinical History

When obtaining a history from the patient with acne, the following details should be sought:

• Are there any local symptoms, such as pain or tenderness?
• Are there any symptoms of infection, such as pus, erythema, fever etc.?
• Are there any other systemic symptoms (e.g. has there been changes in the menstrual cycle, fertility problems etc. as seen with PCOS)?
• Where are the acne lesions predominantly located?
• Have there been any new medications, or cosmetic or chemical applications, applied to the skin?
• Are there any other identifiable aggravating factors for the acne?
• How have the acne lesions impacted the patient psychologically?
• Have there been any prior treatments for acne?

Clinical Examination

A physical examination should be performed in the patient with acne to further assess the situation. Acne is characterised by comedones, papules, pustules, and nodules in a sebaceous distribution. The face may be the only involved skin surface, but the chest, back and upper arms are also often involved.

Comedonal acne

No inflammatory lesions are present. Comedonal lesions are the earliest lesions of acne, and closed comedones are the precursor lesion of inflammatory lesions.⁴

Mild inflammatory acne

Characterised by inflammatory papules and comedones.⁴

Moderate inflammatory acne

Has comedones, inflammatory papules, and pustules.⁴

Nodulocystic acne

Characterised by comedones, inflammatory lesions, and large nodules greater than 5 mm in diameter. This type of acne is commonly associated with widespread scarring.⁴

Specific Investigations

The diagnosis of acne is a clinical diagnosis. However, in a female patient with dysmenorrhoea or hirsutism, a hormonal evaluation should be considered. Patients with evidence of virilisation must have their total testosterone levels measured. Free testosterone, DHEA-S, luteinizing hormone, and follicle-stimulating hormone levels should be measured as appropriate. Skin lesion cultures to rule out gram-negative folliculitis may be warranted when no response to treatment occurs, or when improvement is not maintained.⁴

Prognosis

Most cases of acne will resolve without any scars or further complications. In patients with more severe cases of acne (such as nodulocystic acne), there may be permanent manifestations, including pitting and scarring of the skin. Severe scarring can cause psychological trauma for patients, even to the extreme of being a risk factor for suicide in males.³ Effective treatments are available, so a large majority of scarring may be preventable with early medical intervention.³
Local inflammation can lead to permanent alterations in skin pigmentation, resulting in a darker red or brown hue at the site of healed acne lesions. This occurrence is most frequently seen in patients with darker complexions.⁶

Treatment Overview

Basis of treatment

Treatment of acne is justified for several reasons:³

1. Acne may be aesthetically and sometimes physically (pain, bleeding or discharge) unpleasant. Very rarely, cases of systemic toxicity requiring hospitalisation have been reported.
2. Acne can cause psychological distress in adolescents who are at a vulnerable stage of mental and social development. Acne may cause social disinhibition and poor self-image.
3. Acne may cause severe scarring and long-term psychological trauma. Scarring may affect up to 95% of people with acne, but may be prevented with early intervention. Greater duration and severity of acne prior to treatment increases the risk of scarring.

Aims of treatment

The main goal of treating acne is to eliminate comedone lesions by normalising follicular keratinisation, decreasing sebaceous gland activity, decreasing the population of Proprionobacterium acnes, and decreasing inflammation.
There are both local and systemic medications which can help treat acne. In mild cases of acne, localised topical therapy to the skin should suffice. Although it is recommended that areas of acne should be kept clean, there is little evidence to suggest that removal of surface oils plays an important role in therapy. Vigorous scrubbing of acne should be avoided, due to possible mechanical rupture of comedones and aggravation of acne lesions.¹

Local agents

Topical agents used in the treatment of acne include:

• Adapalene;
• Tretinoin;
• Benzoyl peroxide;
• Salicyclic acid.

These agents act to alter the pattern of epidermal shedding, preventing the formation of comedones and promoting resolution of pre-existing cysts.

Retinoids

Topical retinoids (e.g. adapalene, tretinoin) are primarily comedolytic and anti-inflammatory. They cause epidermal differentiation and result in normalisation of follicular hyperproliferation and hyperkeratinisation.
Topical retinoids should be applied once daily to clean, dry skin, but they may need to be applied less frequently if irritation occurs. These treatments can cause skin irritation with peeling and redness. The use of mild, non-drying cleansers and appropriate moisturisers may help reduce this irritation. If irritation persists, the patient may need to turn to alternate-day dosing.
As a result of prolonged treatment, the stratum corneum may be thinned, resulting in sun hypersensitivity. Extra sun protection should be encouraged in these patients.

Antibacterials

Topical antibacterial agents (e.g. azelaic acid, erythromycin, clindamycin) may be helpful adjuncts in some situations. These agents are mainly used for their role against Propionobacterium acnes. They may also possess some anti-inflammatory properties. However, topical antibacterial agents are not comedolytic and bacterial resistance can develop.
Clindamycin and erythromycin are available in a variety of topical agents. They are usually applied once or twice daily.

Peroxides

Benzoyl peroxide products are effective against Propionobacterium acnes, and bacterial resistance to benzoyl peroxide has not been reported. Benzoyl peroxides are available in a variety of topical forms, including soaps, washes, lotions, gels and creams. Benzoyl peroxides may be used once or twice daily. In some cases, an irritant contact dermatitis develops, especially when benzoyl peroxide products are used with tretinoin, or when accompanied by aggressive scrubbing of the face.⁴

Systemic agents

In patients who suffer from more severe acne and/or the presence of a prominent inflammatory component, systemic therapy may offer more effective treatment.

Antibiotics

Tetracycline antibiotics or erythromycin treat acne by promoting an anti-inflammatory response within acne lesions and inhibiting Propionobacterium acnes. The tetracycline group of antibiotics is commonly prescribed for acne. However, Propionobacterium acnes resistance is becoming more common with all classes of antibiotics currently used to treat acne. Propionobacterium acnes resistance to erythromycin has greatly reduced its usefulness in the treatment of acne.
Other antibiotics (e.g. trimethoprim, sulphamethoxazole, azithromycin) are helpful either alone or in combination. Bacterial resistance to these antibiotics may be reduced by combining them with topical retinoids or benzoyl peroxide.

Hormonal treatments

In female patients who do not respond to oral antibiotics, hormonal therapy with the combined oral contraceptive pill (containing ethynyl oestradiol and a progesterone) has been shown to produce an improvement in acne lesions when compared to placebo. Oral contraceptives increase sex hormone binding globulin, resulting in a decrease in the amount of circulating free testosterone.
Spironolactone may also be helpful in the treatment of acne. It binds the androgen receptor and reduces androgen production. If patients are started on spironolactone, there should be regular blood pressure monitoring, and potassium levels should be periodically evaluated. Advice about avoiding pregnancy is essential due to the risk of feminisation of the male foetus.

Retinoids

Patients with severe nodulocystic acne that is unresponsive to the above medications may benefit from treatment with the synthetic retinoid isotretinoin. It normalises epidermal differentiation, depresses sebum excretion by 70%, displays anti-inflammatory effects, and reduces the presence of Propionobacterium acnes. Isotretinoin therapy should be initiated at a dose of 0.5 mg/kg/day for four weeks and increased as tolerated until a cumulative dose of 120-150 mg/kg is achieved.
If this drug is used, the patient should be closely monitored for adverse effects, especially teratogenicity. There are measures in place to ensure that all prescribers are familiar with the risks of isotretinoin.  All female patients should demonstrate two negative pregnancy tests prior to initiating therapy and a negative pregnancy test prior to each refill. Additionally, patients receiving this medication may develop extremely dry skin, cheilitis, mood disturbances (primarily depression), and must be monitored for development of hypertriglyceridaemia.^2,4

References

1. Buxton P. ABC of Dermatology. London: BMJ Publishing; 2005. [Book]
2. Calvin O, Lawley J. Acne. In: Braunwald E, Fauci AS, Kasper DL, et al. Harrison’s Principles of Internal Medicine (10th edition). New York: McGraw-Hill Publishing; 2006. [Book]
3. Goodman GJ. Acne and acne scarring: Why should we treat? Med J Aust.1999;171(2):62-3. [Full text]
4. Harper J. Acne vulgaris. E-medicine; 2006.
5. Cotran RS, Kumar V, Collins T, Robbins SL. Robbins Pathologic Basis of Disease (6th edition). Philadelphia: WB Saunders Company; 1999. [Book]
6. Murtagh J. General Practice (2nd edition). New York: McGraw-Hill; 1998. [Book]
7. Stathakis V, Kilkenny M, Marks R. Descriptive epidemiology of acne vulgaris in the community. Australas J Dermatol.1997;38(3):115-23. [Abstract]