Information

Acne vulgaris, the common form of Acne, affects large numbers of people (and virtually all adolescents), sometimes with distressing psychosocial effects. The potential market for an effective, easy-to-use, well-tolerated treatment is huge.

A wide range of treatments exists for acne vulgaris, each of which combats particular aspects of the underlying process that results in acne vulgaris. Some of these treatments are applied directly to the skin (topical treatments) and others are taken orally (systemic treatments). To understand how these treatments work, you need to know how the mechanisms that produce acne vulgaris interact.

STRUCTURE AND FUNCTION OF NORMAL SKIN

The skin is one of the heaviest body organs and has a surface area of about 2msq in an adult. The skin has several important physiological functions, including:

• regulation of body temperature

• protection

• sensation

• excretion (via sweat glands)

• synthesis of vitamin D (important in calcium metabolism).

An individual's skin ranges in thickness from 0.5 mm to 4 mm and consists of two layers, the:

• epidermis - the thinner outer layer, which is itself made up of different  layers

• dermis - the thicker inner layer containing nerve endings, glands, blood  vessels, hair follicles
   and other structures.

Beneath the dermis is the fatty subcutaneous layer, which attaches to underlying tissues and organs.

The epidermis contains four main types of cell arranged in a layered structure known as stratified squamous epithelium. About 90% of cells in the epidermis are keratinocytes. These cells produce keratin, a protein that helps waterproof and protect the skin, and that forms hair and nails. Other epidermal cells include:

• Melanocytes, which produce the pigment melanin

• Langerhans cells, which are involved in immune defence

• Merkel cells, which are thought to be involved in the sensation of touch.

The keratinocytes are arranged in four, or in some locations (such as the palms of the hands and soles of the feet, which contain the extra layer of the stratum lucidum) five layers. The deepest layer is called the stratum basale, which contains the stem cells that produce keratinocytes. The young keratinocytes push upwards through the stratum spinosum, to the stratum granulosum and stratum corneum in a process known as keratinisation.

Keratin is incorporated into the keratinocytes in the stratum granulosum and, as their nuclei degenerate, the keratinocytes die. When they reach the stratum corneum, the keratinocytes have flattened and are completely filled with keratin. Eventually they are sloughed off, to be replaced by the next row of keratinocytes.

The whole process of keratinisation takes approximately 2-4 weeks.

DERMIS

The dermis is composed of connective tissue containing blood vessels, collagen and elastin fibres with a few fat cells, macrophages and fibroblasts interspersed. It also contains specialised nerve endings that are sensitive to touch (Meissner's corpuscles), pressure (Pacinian corpuscles), heat and cold. Sweat glands, sebaceous glands and hair follicles are embedded in the dermis and extend through the epidermis to open onto the surface of the skin. A pilosebaceous follicle is a unit consisting of one hair and an associated sebaceous gland.

The Structure of Skin

PILOSEBACEOUS FOLLICLE

There are three kinds of pilosebaceous follicle in the dermis:

 • vellus follicles, comprising a tiny hair and a much larger sebaceous gland

 • sebaceous follicles, comprising a tiny hair and an exceptionally large multiacinar sebaceous
    gland

 • terminal hair follicles, comprising a long, stiff, thick hair and a proportionately sized sebaceous
    gland.

The sebaceous follicles are the only ones involved in acne, although the other types contribute to the amount of lipid on the surface of the skin. Sebaceous follicles are found only on the face, upper arms, chest and upper back, and acne vulgaris can only occur in these areas. Sebaceous glands throughout the body, including those in the sebaceous follicles, produce sebum, an oily substance consisting of a mixture of fats, cholesterol, proteinsand salts. Sebum spreads from the sebaceous follicle onto the hair and skin. It prevents hair from drying out and keeps skin supple. It also inhibits the growth of certain bacteria.

BACTERIAL FLORA OF THE SKIN

The skin comes into contact with a large number of organisms, most of which find the skin a hostile environment and do not survive. However, everyone has a range of bacteria living on their skin as commensals (two or more different organisms sharing the same living space). One of the bacteria found on the skin surface is Propionibacterium acnes, which has an important role in the development of acne. Other micro-organisms that might be involved are Pityrosporum ovale and Staphylococcus epidermidis.

DEVELOPMENT OF ACNE VULGARIS

Acne vulgaris is a disorder of the sebaceous follicles of the face, neck, upper back and upper chest and can be divided into four stages:

• Hypersecretion of sebum

• Abnormal keratinisation and comedone formation

• Bacterial proliferation

• Inflammation

HYPERSECRETION OF SEBUM

Sebum is produced by the sebaceous glands, the activity of which is controlled by the male sex hormones known as androgens. Androgen levels increase at puberty (in both males and females) and this increase results in the enlargement and proliferation of the sebaceous glands. In turn, this results in an increase in the production of sebum, which causes the seborrhoea that is associated with acne. Although the higher androgen levels that are reached during puberty continue into adulthood, many people stop suffering from acne when they leave their adolescence. The reason for this is not fully understood. One explanation is that there is overactivity of sebaceous gland androgen receptors during puberty, in which there is increased local conversion of testosterone (an androgen) to the more potent dihydrotestosterone by the enzyme 5-alpha-reductase. As this overactivity resolves, so does the acne.

ABNORMAL KERATINISATION AND COMEDONE FORMATION

A malfunction of the keratinisation process in the epidermis lining the sebaceous duct can result in a thickening of the epidermis. In combination with sebum and bacteria, the thickened epidermis can block the sebaceous duct with a plug of keratinocytes. Sebum and keratinous debris accumulate behind the blockage and eventually, distension of the sebaceous unit produces readily visible comedones of which there are two types:

• Open comedones (blackheads)

• Closed comedones (whiteheads)

In open comedones, the keratinous plug is relatively large and visible and has a dark surface, hence the name blackhead. The black colouration is due to the accumulation of the pigment melanin; it is not dirt. Open comedones never evolve into acne (as long as they are not squeezed by the patient), probably because the plug is easily overcome by the increased levels of sebum secreted by the follicle. There is, therefore, no invasion of the dermis, and thus no inflammatory changes. In closed comedones, the keratinous plug is small but blocks the sebaceous duct completely. The distension of the sebaceous gland produces a raised white papule.

BACTERIAL PROLIFERATION

Blockage of the sebaceous duct and accumulation of sebum creates the anaerobic conditions in which the bacterium P. acnes produces various enzymes, which split sebum into free fatty acids, which have been found to assist in the formation of comedones. Free fatty acids induce inflammation if they escape into the dermis.

INFLAMMATION GLOSSARY

The proliferating P. acnes also release factors (free fatty acids) that diffuse through the walls of the pilosebaceous gland and attract neutrophils. The neutrophils enter the pilosebaceous gland where they engulf and destroy (phagocytose) the bacteria. During this process they release enzymes (e.g. liposes) which attack and disrupt the walls of the gland, destroying bacteria causing it to rupture. This allows the contents of the unit, including free fatty acids and bacteria, to spread into the dermis where they produce an inflammatory response. The inflammation produces redness, swelling and pain. The severity of the resulting lesion depends on the extent of the damage and ranges from a small pustule to a large nodule or cyst. Healing of the lesions, particularly the more severe lesions, may produce the typical pitted scarring. Occasionally, the scar becomes thickened and raised due to excess production of collagen. These are known as keloid scars.

OTHER CONTRIBUTORY FACTORS

Genetic factors have an important influence on the severity, duration and clinical pattern of conditions of comedones and produce acne vulgaris.

DIAGNOSIS OF ACNE VULGARIS

The diagnosis of acne vulgaris is usually straightforward, being based on the presence of comedones with or without papules, pustules, nodules, cysts and scarring occurring in a typical distribution. Comedones are the most important diagnostic feature. Investigations are not usually required to confirm the diagnosis. Occasionally, fluid from acne lesions is cultured to exclude other forms of skin infection.

GRADING OF ACNE VULGARIS

Grading acne vulgaris is a means of assessing the severity of this highly variable condition. The techniques used can provide useful information to monitor the variation of the condition over time and the effect of treatment in individuals. Importantly, grading techniques can also facilitate the conduct of clinical trials and comparisons between completed trials. However, there is no standard acne grading system.

Several grading systems have been developed. The simplest of these is a system that classifies the condition as being mild, moderate or severe:

• mild - open and closed comedones, some papules and pustules

• moderate - comedones with more frequent papules and pustules with  mild scarring

• severe- comedones, papules, pustules, nodular abscesses and scarring (sometimes keloidal)

THE LEEDS SYSTEM

This system involves evaluating the acne severity using a counting (of lesions) technique. The scale extends from 0 (no acne whatsoever) to 10 (the most severe acne). A photographic reference standard is available for correct interpretation.

COOK SYSTEM

The Cook system is a well known system that involves evaluating the overall severity of the acne on a 0 to 8 scale anchored to photographic standards that illustrate grades 0, 2, 4, 6 and 8.

COOK GRADING SCALE FOR OVERALL

Severity of Acne	Grade Description
0	Need not be perfect; 3 small comedones and/or papules are permitted, if they are scattered
2	Very few pustules, up to 3 dozen papules and/or comedones; no big or prominent lesions; lesions are hardly visible from 2.5m away
4	Between grades 2 and 6. Red lesions and inflammation are present to a significant degree. Worthy of treatment
6	Numerous comedones, but no inflammation or inflammatory lesions, numerous pustules, lesions easily recognised at 2.5m, some pustules may be quite large (1-2 cm)
8	Conglobata, sinus or cystic type acne or Highly inflammatory acne covering most of the face; yellow pustules extend to neck and chin.

FREQUENTLY USED ACNE GRADING SYSTEMS

Other grading systems used in acne are:

• Allen and Smith

• Cunliffe

• Cutler

• Pillsbury

• Plewig and Kligman

MANAGEMENT OF ACNE VULGARIS

This section outlines the principles of the management of acne vulgaris and explains the mode of action, advantages and disadvantages of the range of treatments used.

AIMS OF TREATMENT

Treatment of acne vulgaris aims to:

• limit disease duration

• reduce the psychological impact of the condition

• prevent scarring.

MEDICAL ATTITUDES TO ACNE VULGARIS

The attitude of physicians to acne vulgaris can vary tremendously. Some take the attitude that it is a 'normal physiological process' and that the sufferer just has to wait to 'grow out of it'. Others, in particular dermatologists, take a more proactive and sympathetic stance and are keen to treat the condition.

NON-DRUG MEASURES

Washing twice daily to remove surface sebum is generally advised to improve appearance. However, it has no impact on existing or future acne lesions. In addition, the washing may dry-out the skin if too frequent (for example, more than twice a day). Patients are also advised to:

• avoid greasy make-up, as it will block the follicle outlet

• remove make-up thoroughly at night

• avoid squeezing their spots (as this may force sebum deep into the skin and cause
   inflammation followed by scarring).

Large blackheads can be removed using a special implement called a comedone spoon. Counselling is often helpful in enhancing compliance with any treatment and to counter any misconceptions about the condition.

DRUG TREATMENTS

A very wide range of treatments is available for acne vulgaris, some of which are applied to the surface of the skin (topical treatments) and some of which are taken orally (systemic treatments). They vary in their mode of action and side effects.

The severity of the acne is the most powerful factor in choosing a particular treatment. Topical treatments are usually used in mild and moderate acne, and systemic treatments (with or without topical co-therapy) are usually used in the treatment of severe acne. Systemic treatments may also be used in mild and moderate acne if topical treatments do not produce the desired improvement. Co-prescription (topical and oral) occurs regularly in more severe cases of acne. However, the Practical Support for Clinical Governance (Prodigy) suggests topical antibiotics should not be used concurrently with oral antibiotics because of problems of antibiotic resistance.

Factors other than severity may have a role in determining the most appropriate treatment. For example it may be justified to use a systemic treatment for a patient with mild acne who is very distressed by it. A systemic treatment would also be more appropriate for a patient with acne on his/her back who could find it difficult to apply a topical treatment. Furthermore, care should be taken when prescribing systemic treatments for women of child-bearing age; a topical therapy may be more appropriate.

APPROACHES TO DRUG TREATMENT

The treatments used for acne vulgaris attack different aspects of the underlying pathogenesis of the condition.

Most treatments for acne vulgaris may take several weeks, if not months, to achieve maximal efficacy. Furthermore, most treatments do not alter the natural course of the disease: they suppress its manifestations until the disease resolves of its own accord. As a result, an effective treatment needs to be continued for prolonged periods.

TOPICAL TREATMENTS

Topical treatments are applied to the whole area affected by acne vulgaris, not just to the acne lesions currently visible. The potential advantages of topical treatment over systemic antibiotics include more appropriate targeting of the affected area, higher skin concentrations of antibiotic, a theoretically lower risk of systemic side-effects and fewer interactions with other therapies. Many topical treatments contain combinations of therapeutic agents, each of which treats acne via a different mode of action. Topical antibiotics usually require a prescription.

BENZOYL PEROXIDE (e.g. Brevoxyl, Panoxyl)

Benzoyl peroxide is available as creams and gels (2.5-10%), and also soaps and washes.

Benzoyl peroxide is not an antibiotic, although it does have a bactericidal action and reduces the number of P. acnes in the skin. It also breaks down keratin and comedones; it may also suppress sebum production. In combination with the antibiotic erythromycin or clindamycin, benzoyl peroxide helps to prevent the development of antibiotic resistance by bacteria. The major adverse effect of benzoyl peroxide is skin irritation, including contact dermatitis, which often subsides if the frequency of application is reduced. It can also bleach hair and clothes.

TRETINOIN (e.g. Retin-A)

Topical tretinoin (also known as retinoic acid) is a derivative of vitamin A. It is available as lotions, creams and gels (0.025% and 0.1%). Tretinoin acts by stimulating the division and turnover of keratinocytes. It also reduces the cohesiveness ('stickiness') of the keratinocytes, promoting the disappearance of comedones by dissolving the keratin plugs and inhibiting the formation of new ones. Removal of the comedone makes the sebaceous unit more aerobic and discourages the proliferation of P. Acnes. In addition, tretinoin suppresses the activity of sebaceous glands. Tretinoin has exfoliating effects and may cause skin irritation and peeling, but this is usually a transient effect. Topical retinoids should be avoided in severe acne involving large areas of the body, and should be used with caution on sensitive areas such as the neck. In patients with inflammatory lesions as well as comedones, antibiotics or benzoyl peroxide may also be needed.

Tretinoin may cause photosensitivity. Therefore, it is usually recommended to apply tretinoin in the evening, although many preparations are licensed for twice daily application.

ANTIBIOTICS

The topical antibiotics used most frequently for the treatment of acne are erythromycin and clindamycin, although tetracycline is also used. They are available as lotions, creams and gels (1-4%) and are useful for treating the inflammatory aspects of acne vulgaris, but in general have no comedolytic effects. Many cases of acne have a combination of comedones and inflammatory lesions, and antibiotics are sometimes combined with a comedolytic product such as tretinoin for a more rapid effect, e.g. Isotrexin.

Antibiotics improve acne by reducing the population of P. acnes in the skin. They also have anti-inflammatory effects by suppressing the migration of white blood cells to the inflamed areas. Antibiotics may also inhibit certain enzymes, which will reduce the proportion of free fatty acids, therefore reducing the amount of inflammation.

Topical antibiotics have fewer systemic side-effects, and are found in higher therapeutic levels in the follicle than their oral counterparts, which act systemically. However, the alcohol base used in some formulations may cause burning or stinging when applied to the skin and some patients develop hypersensitivity to the antibiotic itself. A residue left by topical tetracycline may fluoresce under ultraviolet (e.g. disco) lights. (e.g. Topicycline)

It seems that in vitro resistance of P. acnes to antibiotic therapy is increasing and may be the explanation for poor response to antibiotics in some patients. However, this is not usually the case, perhaps for the following reasons:

• patients may have a mixture of resistant and non-resistant bacteria on their skins, therefore
   patients might improve with appropriate treatment

• topical antibiotics do not need to eliminate all bacteria

• resistance is usually defined in the laboratory on the basis of the minimum inhibitory
   concentration (MIC) of the antibiotic required to inhibit multiplication of the bacterium. It is
   possible that some topical preparations achieve concentrations in the sebaceous gland that
   exceed the MIC and so reduce bacterial numbers.

Confirmation that laboratory resistance of bacteria does not necessarily correlate with clinical inefficacy has been demonstrated in an in vitro study with topical erythromycin and topical erythromycin/zinc combination. In the study, this combination produced significant reductions in the number of both resistant and non-resistant bacteria.

OTHER TOPICAL AGENTS

AZELAIC ACID is a dicarboxylic acid with antimicrobial and anticomedonal properties. It has been reported to cause alterations in the free fatty acid content of the skin, and significantly reduces bacterial colonisation. Some patients prefer this agent to benzoyl peroxide because it is likely to cause local irritation.

NICOTINAMIDE can be used to treat inflammatory acne: side-effects include skin dryness as well as redness, burning and irritation.

SALICYLIC ACID can be used for its keratolytic effect in patients who cannot tolerate retinoids, and there are several over-the-counter preparations, but it is considered less suitable for prescribing.

Preparations containing sulphur and abrasive agents are not considered beneficial in acne, and topical corticosteroids should not be used.


TOPICAL COMBINATION PRODUCTS

More than one topical agent maybe used in the treatment of acne, either combined in one product or as separate products used sequentially. These agents may have synergistic effects and produce enhanced efficacy as a result.

SYSTEMIC TREATMENTS

The BNF (British National Formulary) recommends systemic antibacterial treatment for inflammatory acne where topical treatment is not adequately effective or where it is inappropriate. For example, this may be the case where the back is affected, making application of a topical treatment impractical.

ORAL TREATMENTS

ORAL ANTIBIOTICS

Oral antibiotics are the most widely used systemic therapy for acne vulgaris. Tetracycline and minocycline have traditionally been the most commonly used systemic antibiotics for acne; erythromycin, doxycycline and co-trimoxazole are also used. The topical antibiotic clindamycin is not used systemically because of the risk of pseudomembranous colitis The antibiotics have bactericidal/bacteriostatic and anti-inflammatory effects.

The need for long-term treatment may increase the incidence of side effects from oral antibiotics. The oral antibiotics can cause gastrointestinal problems and should not be used during pregnancy and lactation. Furthermore:

• tetracycline should not be used in children under 12 years because it can discolour the
   deciduous teeth

• minocycline can also discolour the teeth and can cause vertigo-like symptoms and
   tinnitus.There are also concerns over its ability to
   produce more severe side effects, such as drug-induced hepatitis and
   systemic lupus erythematosus*

• doxycycline has similar contraindications to tetracycline and can cause photosensitivity

• co-trimoxazole can cause bone marrow suppression. This is an unlicensed treatment for acne

• Chronic inflammatory disease of connective tissue

ORAL ISOTRETINOIN (ROACCUTANE)

Isotretinoin is an oral vitamin A derivative. It is highly effective in the treatment of severe acne. It:

• is thought to act by reducing the size of and amount of secretion from sebaceous glands

• reduces keratinisation

• has anti-inflammatory effects.

A course of treatment is usually 16-20 weeks long and it may take several weeks for an effect to become apparent. However, improvement may continue after cessation of therapy and the remission may last for months or years. Because of possible severe adverse effects, isotretinoin can only be prescribed by, or under the supervision of, a consultant dermatologist.The side effects of isotretinoin include: dry skin and mucous membranes, cheilitis, dry eyes, nose bleeds, diminished night vision, photosensitivity, hair loss, aching joints and headache. Because it is highly teratogenic, isotretinoin should not be used in women of child-bearing age who are not using contraceptives.

In the UK oral isotretinoin can only be prescribed by secondary care specialists.

HORMONAL THERAPIES

Hormonal therapies may be used in women with severe acne that is refractory to other forms of treatment. The antiandrogen cyproterone acetate reduces sebum production. Cyproterone acetate is usually administered with oestrogen to provide effective contraceptive cover as it will feminise a male fetus, e.g. Dianette. High-dose oestrogen oral contraceptives improve acne by reducing the size of the sebaceous gland, and so reducing sebum production.

OTHER TREATMENTS

Other measures used in the treatment of acne vulgaris include:

• removal of comedones

• injection of triamcinolone or other corticosteroids into large, severely inflamed cysts and
   nodules

• excision of scars and persistent cysts

• injections of collagen into depressed scars to raise them to the usual skin level

• dermabrasion - removal of a layer of epidermis including scars, the epidermis then
   regenerates.

SUMMARY

• The skin is composed of two layers: the dermis and the epidermis.

• Acne is a disorder of the sebaceous follicle - the anatomical structure that consists of a hair
   follicle and a sebaceous gland.

• Sebaceous glands produce sebum, a mixture of fats and oils.

• The pathogenesis of acne vulgaris has four stages: hypersecretion of sebum, abnormal
   keratinisation and comedone formation, bacterial proliferation and inflammation.

• Several systems exist for the grading of acne vulgaris, including a simple mild-moderate-
   severe system and the more complex Cook and Leeds systems. There is no standard grading
   system.

• The treatment of acne vulgaris aims to limit disease duration, reduce the psychological impact
   of the condition and prevent scarring.

• The severity of the acne is the most powerful factor for determining the type and formulation
   of the treatment used. In general, topical treatments are used for mild and moderate acne,
   and oral treatments are used for severe acne and those types of acne that do not respond to
   topical therapy.

• Topical agents include: benzoyl peroxide, tretinoin, antibiotics, azelaic acid and exfoliants.
   These may be administered in combination.

• Systemic treatments include: oral antibiotics, isotretinoin and hormonal therapies, including
   oral contraceptives.

Page updated: 9 May 2008