Acne vulgaris

This is a background article.

Acne vulgaris is a skin disorder.

Causes of acne
Acne develops as a result of blockages in follicles. Hyperkeratinization and formation of a plug of keratin and sebum (a microcomedo) is the earliest change. Enlargement of sebaceous glands and an increase in sebum production occur with increased androgen (DHEA-S) production at adrenarche. The microcomedo may enlarge to form an open comedo (blackhead) or closed comedo (whitehead). Whiteheads are the direct result of skin pores becoming clogged with sebum, a naturally occurring oil, and dead skin cells. In these conditions the naturally occurring largely commensal bacteria Propionibacterium acnes can cause inflammation, leading to inflammatory lesions (papules, infected pustules, or nodules) in the dermis around the microcomedo or comedo, which results in redness and may result in scarring or hyperpigmentation.

Primary causes
The root cause of why some people get acne and some do not is not fully known. It is known to be partly hereditary. Several factors are known to be linked to acne:


 * Family/Genetic history. The tendency to develop acne runs in families. For example, school-age boys with acne often have other members in their family with acne as well. A family history of acne is associated with an earlier occurrence of acne and an increased number of retentional acne lesions.
 * Hormonal activity, such as menstrual cycles and puberty. During puberty, an increase in male sex hormones called androgens cause the glands to get larger and make more sebum.
 * Inflammation, skin irritation or scratching of any sort will activate inflammation. Anti-inflammatories are known to improve acne.
 * Stress, through increased output of hormones from the adrenal (stress) glands, although modern tests have said otherwise and point to this not being a cause.
 * Hyperactive sebaceous glands, secondary to the three hormone sources above.
 * Accumulation of dead skin cells that block or cover pores.
 * Bacteria in the pores. Propionibacterium acnes (P. acnes) is the anaerobic bacterium that causes acne. In-vitro resistance of P. acnes to commonly used antibiotics has been increasing.
 * Use of anabolic steroids.
 * Any medication containing lithium, barbiturates or androgens.
 * Exposure to certain chemical compounds. Chloracne is particularly linked to toxic exposure to dioxins, namely Chlorinated dioxins.
 * Exposure to halogens. Halogen acne is linked to exposure to halogens (e.g. iodides, chlorides, bromides, fluorides).
 * Chronic use of amphetamines.

Several hormones have been linked to acne: the androgens testosterone, dihydrotestosterone (DHT) and dehydroepiandrosterone sulfate (DHEAS), as well as insulin-like growth factor 1 (IGF-I). In addition, acne-prone skin has been shown to be insulin resistant.

Development of acne vulgaris in later years is uncommon, although this is the age group for Rosacea which may have similar appearances. True acne vulgaris in adult women may be a feature of an underlying condition such as pregnancy and disorders such as polycystic ovary syndrome or the rare Cushing's syndrome. Menopause-associated acne occurs as production of the natural anti-acne ovarian hormone estradiol fails at menopause. The lack of estradiol also causes thinning hair, hot flashes, thin skin, wrinkles, vaginal dryness, and predisposes to osteopenia and osteoporosis as well as triggering acne (known as acne climacterica in this situation).

Diet
Many patients hold the belief that their acne is influenced by dietary factors, while in previous decades, doctors thought that diet had little influence on acne. There is surprisingly little good scientific evidence to support or refute diet as a factor influencing acne. Most dermatologists are awaiting confirmatory research linking diet and acne but some support the idea that acne sufferers should experiment with their diets, and refrain from consuming such fare if they find such food affects the severity of their acne. This also applies to the belief that eating chocolate directly causes acne.

Milk
Recently, three epidemiological studies from the same group of scientists found an association between acne and consumption of partially skimmed milk, instant breakfast drink, sherbet, cottage cheese, and cream cheese. The researchers hypothesize that the association may be caused by hormones (such as several sex hormones and bovine insulin-like growth factor 1 (IGF-1)) or even iodine present in cow milk. Some but not all of these products survive digestion and could have biological effects in humans. Though there is evidence of an association between milk and acne, the exact cause remains unclear.

Carbohydrates
The long-held belief that there is no link between diets high in refined sugars and processed foods and acne has recently been challenged. The previous belief was based on earlier studies (some using chocolate and Coca Cola) that were methodologically flawed. The recent low glycemic-load hypothesis postulates that rapidly digested carbohydrate foods (such as soft drinks, sweets, white bread) produce an overload in blood glucose (hyperglycemia) that stimulates the secretion of insulin, which in turn triggers the release of IGF-1. IGF-1 has direct effects on the pilosebaceous unit (and insulin at high concentrations can also bind to the IGF-1 receptor) and has been shown to stimulate hyperkeratosis and epidermal hyperplasia. These events facilitate acne formation. Sugar consumption might also influence the activity of androgens via a decrease in sex hormone-binding globulin concentration.

In support of this hypothesis, a randomized controlled trial of a low glycemic-load diet improved acne and reduced weight, androgen activity and levels of insulin-like growth factor binding protein-1. High IGF-1 levels and mild insulin resistance (which causes higher levels of insulin) had previously been observed in patients with acne. High levels of insulin and acne are also both features of polycystic ovarian syndrome.

According to this hypothesis, the absence of acne in some non-Westernized societies could be explained by the low glycemic index of these cultures' diets. It is possible that genetic reasons account for there being no acne in these populations, although similar populations (such as South American Indians or Pacific Islanders) do develop acne. Note also that the populations studied consumed no milk or other dairy products.

Further research is necessary to establish whether a reduced consumption of high-glycemic foods, or treatment that results in increased insulin sensitivity (like metformin) can significantly alleviate acne, though consumption of high-glycemic foods should in any case be kept to a minimum, for general health reasons. Avoidance of "junk food" with its high fat and sugar content is also recommended.

Vitamins A and E
Studies have shown that newly diagnosed acne patients tend to have lower levels of vitamin A circulating in their bloodstream than those who are acne free. In addition people with severe acne also tend to have lower blood levels of vitamin E.

Hygiene
Acne is not caused by dirt. This misconception probably comes from the fact that blackheads look like dirt stuck in the openings of pores. The black color is not dirt but simply oxidised keratin. In fact, the blockages of keratin that cause acne occur deep within the narrow follicle channel, where it is impossible to wash them away. These plugs are formed by the failure of the cells lining the duct to separate and flow to the surface in the sebum created there by the body. Built-up oil of the skin can block the passages of these pores, so standard washing of the face could wash off old oil and help unblock the pores.

Available treatments
There are many products available for the treatment of acne, many of which are without any scientifically-proven effects. Generally speaking, successful treatments show little improvement within the first two weeks, instead taking a period of approximately three months to improve and start flattening out. Many treatments that promise big improvements within two weeks are likely to be largely disappointing. However, short bursts of cortisone can give very quick results, and other treatments can rapidly improve some active spots, but usually not all active spots.

Modes of improvement are not necessarily fully understood but in general treatments are believed to work in at least 4 different ways (with many of the best treatments providing multiple simultaneous effects):
 * normalising shedding into the pore to prevent blockage
 * killing Propionibacterium acnes
 * anti-inflammatory effects
 * hormonal manipulation

A combination of treatments can greatly reduce the amount and severity of acne in many cases. Those treatments that are most effective tend to have greater potential for side effects and need a greater degree of monitoring, so a step-wise approach is often taken. Many people consult with doctors when deciding which treatments to use, especially when considering using any treatments in combination. There are a number of treatments that have been proven effective:



Topical bactericidals
Widely available OTC bactericidal products containing benzoyl peroxide may be used in mild to moderate acne. The gel or cream containing benzoyl peroxide is rubbed, twice daily, into the pores over the affected region. Bar soaps or washes may also be used and vary from 2 to 10% in strength. In addition to its therapeutic effect as a keratolytic (a chemical that dissolves the keratin plugging the pores) benzoyl peroxide also prevents new lesions by killing P. acnes. In one study, roughly 70% of participants using a 10% benzoyl peroxide solution experienced a reduction in acne lesions after 6 weeks. Unlike antibiotics, benzoyl peroxide has the advantage of being a strong oxidizer (essentially a mild bleach) and thus does not appear to generate bacterial resistance. However, it routinely causes dryness, local irritation and redness. A sensible regimen may include the daily use of low-concentration (2.5%) benzoyl peroxide preparations, combined with suitable non-comedogenic moisturisers to help avoid overdrying the skin.

Care must be taken when using benzoyl peroxide, as it can very easily bleach any fabric or hair it comes in contact with.

Other antibacterials that have been used include triclosan, or chlorhexidine gluconate. Though these treatments are often less effective, they also have fewer side-effects.

Prescription-strength benzoyl peroxide preparations do not necessarily differ with regard to the maximum concentration of the active ingredient (10%), but the drug is made available dissolved in a vehicle that more deeply penetrates the pores of the skin.

Topical antibiotics
Externally applied antibiotics such as erythromycin, clindamycin, stievamycin, or tetracycline kill the bacteria that are harbored in the blocked follicles. While topical use of antibiotics is equally as effective as oral use, this method avoids possible side effects including upset stomach and drug interactions (e.g. it will not affect use of the oral contraceptive pill), but may prove awkward to apply over larger areas than just the face alone.

Oral antibiotics
Oral antibiotics used to treat acne include erythromycin or one of the tetracycline antibiotics (tetracycline, the better absorbed oxytetracycline, or one of the once daily doxycycline, minocycline, or lymecycline). Trimethoprim is also sometimes used (off-label use in UK). However, reducing the P. acnes bacteria will not, in itself, do anything to reduce the oil secretion and abnormal cell behaviour that is the initial cause of the blocked follicles. Additionally the antibiotics are becoming less and less useful as resistant P. acnes are becoming more common. Acne will generally reappear quite soon after the end of treatment&mdash;days later in the case of topical applications, and weeks later in the case of oral antibiotics. Furthermore side effects of tetracycline antibiotics can include yellowing of the teeth and an imbalance of gut flora, so are only recommended after topical products have been ruled out.

It has been found that sub-antimicrobial doses of antibiotics such as minocycline also improve acne. It is believed that minocycline's anti-inflammatory effect also prevents acne. These low doses do not kill bacteria and hence cannot induce resistance.

Hormonal treatments
In females, acne can be improved with hormonal treatments. The common combined oestrogen/progestogen methods of hormonal contraception have some effect, but the antiandrogen, Cyproterone, in combination with an oestrogen (Diane 35) is particularly effective at reducing androgenic hormone levels. Diane-35 is not available in the USA, but a newer oral contraceptive containing the progestin drospirenone is now available with fewer side effects than Diane 35 / Dianette. Both can be used where blood tests show abnormally high levels of androgens, but are effective even when this is not the case. Along with this, treatment with low dose spironolactone can have anti-androgenetic properties, especially in patients with polycystic ovarian syndrome.

If a pimple is large and/or does not seem to be affected by other treatments, a dermatologist may administer an injection of cortisone directly into it, which will usually reduce redness and inflammation almost immediately. This has the effect of flattening the pimple, thereby making it easier to cover up with makeup, and can also aid in the healing process. Side effects are minimal, but may include a temporary whitening of the skin around the injection point; and occasionally a small depression forms, which may persist, although often fills eventually. This method also carries a much smaller risk of scarring than surgical removal.

Topical retinoids
A group of medications for normalizing the follicle cell lifecycle are topical retinoids such as tretinoin (brand name Retin-A), adapalene (brand name Differin), and tazarotene (brand name Tazorac). Like isotretinoin, they are related to vitamin A, but they are administered as topicals and generally have much milder side effects. They can, however, cause significant irritation of the skin. The retinoids appear to influence the cell creation and death lifecycle of cells in the follicle lining. This helps prevent the hyperkeratinization of these cells that can create a blockage. Retinol, a form of vitamin A, has similar but milder effects and is used in many over-the-counter moisturizers and other topical products. Effective topical retinoids have been in use over 30 years but are available only on prescription so are not as widely used as the other topical treatments. Topical retinoids often cause an initial flare up of acne and facial flushing.

Oral retinoids
A daily oral intake of vitamin A derivative isotretinoin (marketed as Accutane, Amnesteem, Sotret, Claravis, Clarus) over a period of 4-6 months can cause long-term resolution or reduction of acne. It is believed that isotretinoin works primarily by reducing the secretion of oils from the glands, however some studies suggest that it affects other acne-related factors as well. Isotretinoin has been shown to be very effective in treating severe acne and can either improve or clear well over 80% of patients. The drug has a much longer effect than anti-bacterial treatments and will often cure acne for good. The treatment requires close medical supervision by a dermatologist because the drug has many known side effects (many of which can be severe). About 25% of patients may relapse after one treatment. In those cases, a second treatment for another 4-6 months may be indicated to obtain desired results. It is often recommended that one lets a few months pass between the two treatments, because the condition can actually improve somewhat in the time after stopping the treatment and waiting a few months also gives the body a chance to recover. Occasionally a third or even a fourth course is used, but the benefits are often less substantial. The most common side effects are dry skin and occasional nosebleeds (secondary to dry nasal mucosa). Oral retinoids also often cause an initial flare up of acne within a month or so, which can be severe. There are reports that the drug has damaged the liver of patients. For this reason, it is recommended that patients have blood samples taken and examined before and during treatment. In some cases, treatment is terminated or reduced due to elevated liver enzymes in the blood, which might be related to liver damage. Others claim that the reports of permanent damage to the liver are unsubstantiated, and routine testing is considered unnecessary by some dermatologists. Blood triglycerides also need to be monitored. However, routine testing are part of the official guidelines for the use of the drug in many countries. Some press reports suggest that isotretinoin may cause depression but as of September 2005 there is no agreement in the medical literature as to the risk. The drug also causes birth defects if women become pregnant while taking it or take it while pregnant. For this reason, female patients are required to use two separate forms of birth control or vow abstinence while on the drug. Because of this, the drug is supposed to be given to females as a last resort after milder treatments have proven insufficient. Restrictive rules (see iPledge program) for use were put into force in the USA beginning in March 2006 to prevent misuse, causing occasioned widespread editorial comment.

'Blue' and red light
It has long been known that short term improvement can be achieved with light. Although sunlight can kill off bacteria on the skin of the face it supposedly damages the follicular walls lining pores which can actually cause acne 3-4 weeks later, as claimed by acne-review.com. Recently, visible light has been successfully employed to treat acne (phototherapy) - in particular intense violet light (405-420nm) generated by purpose-built fluorescent lighting, dichroic bulbs, LEDs or lasers. Used twice weekly, this has been shown to reduce the number of acne lesions by about 64%; and is even more effective when applied daily. The mechanism appears to be that a porphyrin (Coproporphyrin III) produced within P. acnes generates free radicals when irradiated by 420nm and shorter wavelengths of light. Particularly when applied over several days, these free radicals ultimately kill the bacteria. Since porphyrins are not otherwise present in skin, and no UV light is employed, it appears to be safe, and has been licensed by the U.S. FDA. The treatment apparently works even better if used with red visible light (660 nanometer) resulting in a 76% reduction of lesions after 3 months of daily treatment for 80% of the patients; and overall clearance was similar or better than benzoyl peroxide. Unlike most of the other treatments few if any negative side effects are typically experienced, and the development of bacterial resistance to the treatment seems very unlikely. After treatment, clearance can be longer lived than is typical with topical or oral antibiotic treatments; several months is not uncommon. The equipment or treatment, however, is relatively new and reasonably expensive to buy initially, although the total cost of ownership can be similar to many other treatment methods (such as the total cost of benzoyl peroxide, moisturizer, washes) over a couple of years of use.

Photodynamic therapy
In addition, basic science and clinical work by dermatologists Yoram Harth and Alan Shalita and others has produced evidence that intense blue/violet light (405-425 nanometer) can decrease  the  number of  inflammatory acne lesion by 60-70%  in 4 weeks of therapy, particularly when the P. acnes is pretreated with delta-aminolevulinic acid (ALA), which increases the production of porphyrins. However this photodynamic therapy is controversial and apparently not published in a peer reviewed journal. A phase II trial, while it showed improvement occurred, failed to show improved response compared to the blue/violet light alone.

Laser treatment
Laser surgery has been in use for some time to reduce the scars left behind by acne, but research has been done on lasers for prevention of acne formation itself. The laser is used to produce one of the following effects:
 * to burn away the follicle sac from which the hair grows
 * to burn away the sebaceous gland which produces the oil
 * to induce formation of oxygen in the bacteria, killing them

Since lasers and intense pulsed light sources cause thermal damage to the skin, there are concerns that laser or intense pulsed light treatments for acne will induce hyperpigmented macules (spots) or cause long-term dryness of the skin.

In the United States, the FDA has approved several companies, such as Candela Corp., to use a cosmetic laser for the treatment of acne. However, efficacy studies have used very small sample sizes (fewer than 100 subjects) for periods of six months or less, and have shown contradictory results. Also, laser treatment being relatively new, protocols remain subject to experimentation and revision, and treatment can be quite expensive. Also, some Smoothbeam laser devices had to be recalled due to coolant failure, which resulted in painful burn injuries to patients.

Dietary Treatments
Though there is little solid scientific evidence showing a connection between diet and acne, many suggest the restriction of certain foods can cause a reduction or elimination in acne. Raw food diets, as well as those not containing meat, dairy, salt, eggs and processed foods are frequently suggested.

Less widely used treatments

 * Shaving off facial hair may reduce the amount of dead skin cells that can become trapped in pores. Shaving may also slightly reduce dryness of the skin after washing. Some support this idea.
 * Aloe vera: there are treatments for acne mentioned in Ayurveda using herbs such as Aloe vera, Neem Haldi (Turmeric) and Papaya. There is limited evidence from medical studies on some of these products, although others have been proven effective. Products from Rubia cordifolia, Curcuma longa (commonly known as Turmeric), Hemidesmus indicus (known as ananthamoola or anantmula), and Azadirachta indica (Neem) have been shown to have anti-inflammatory effects, but not aloe vera.
 * Azelaic acid (brand names Azelex, Finevin and Skinoren) is suitable for mild, comedonal acne.
 * Heat: local heating may be used to kill the bacteria in a developing pimple and so speed healing.
 * Naproxen or ibuprofen are used for some moderate acne for their anti-inflammatory effect.
 * Nicotinamide, (Vitamin B3) used topically in the form of a gel, has been shown in a 1995 study to be more effective than a topical antibiotic used for comparison, as well as having fewer side effects. Topical nicotinamide is available both on prescription and over-the-counter. The property of topical nicotinamide's benefit in treating acne seems to be its anti-inflammatory nature. It is also purported to result in increased synthesis of collagen, keratin, involucrin and flaggrin.
 * Tea tree oil (melaleuca oil) dissolved in a carrier (5% strength) has been used with some success, where it is comparable to benzoyl peroxide but without excessive drying, kills P. acnes, and has been shown to be an effective anti-inflammatory in skin infections.
 * Rofecoxib was shown to improve premenstrual acne vulgaris in a placebo controlled study.
 * Zinc: Orally administered zinc gluconate has been shown to be effective in the treatment of inflammatory acne, although less so than tetracyclines.
 * Comedo extraction
 * Pantothenic acid, (Vitamin B5)

History of some acne treatments
The history of acne reaches back to the dawn of recorded history. In Ancient Egypt, it is recorded that several pharaohs were acne sufferers. From Ancient Greece comes the English word 'acne' (meaning 'point' or 'peak'). Acne treatments are also of considerable antiquity:
 * Ancient Rome: bathing in hot, and often sulfurous, mineral water was one of the few available acne treatments. One of the earliest texts to mention skin problems is De Medicina by the Roman writer Celsus.
 * 1800s: Nineteenth century dermatologists used sulphur in the treatment of acne. It was believed to dry the skin.
 * 1920s: Benzoyl Peroxide is used
 * 1930s: Laxatives were used as a cure for what were known as 'chastity pimples'. Radiation also was used.
 * 1950s: When antibiotics became available, it was discovered that they had beneficial effects on acne. They were taken orally to begin with. Much of the benefit was not from killing bacteria but from the anti-inflammatory effects of tetracycline and its relatives. Topical antibiotics became available later.
 * 1970s: Tretinoin (original Trade Name Retin A) was found effective for acne. This preceded the development of oral isotretinoin (sold as Accutane and Roaccutane) in 1980.
 * 1980s: Accutane is introduced in the United States, and later found to be a teratogen, highly likely to cause birth defects if taken during pregnancy. In the United States more than 2,000 women became pregnant while taking the drug between 1982 and 2003, with most pregnancies ending in abortion or miscarriage. About 160 babies with birth defects were born.
 * 1990s: Laser treatment introduced
 * 2000s: Blue/red light therapy

Future treatments
A vaccine against inflammatory acne has been tested successfully in mice, but it is not certain that it would work similarly in humans. A 2007 microbiology article reporting the first genome sequencing of a Propionibacterium acnes bacteriophage (PA6) said this "should greatly enhance the development of a potential bacteriophage therapy to treat acne and therefore overcome the significant problems associated with long-term antibiotic therapy and bacterial resistance."

Preferred treatments by types of acne vulgaris

 * Comedonal (non-inflammatory) acne: local treatment with azelaic acid, salicylic acid, topical retinoids, benzoyl peroxide.
 * Mild papulo-pustular (inflammatory) acne: benzoyl peroxide or topical retinoids, topical antibiotics (such as erythromycin).
 * Moderate inflammatory acne: benzoyl peroxide or topical retinoids combined with oral antibiotics (tetracyclines). Isotretinoin is an option.
 * Severe inflammatory acne, nodular acne, acne resistant to the above treatments: isotretinoin also known as Accutane, can be prescribed by a doctor, or contraceptive pills with cyproterone for females with virilization or drospirenone.

Acne scars

 * See Acne scarring.

Acne often leaves small scars where the skin gets a "volcanic" shape.

Physical acne scars are often referred to as "Icepick" scars. This is because the scars tend to cause an indentation in the skin's surface. There are a range of treatments available. Although quite rare, the medical condition Atrophia Maculosa Varioliformis Cutis results in "acne like" depressed scars on the face.

Ice pick scars - Deep pits, that are the most common and a classic sign of acne scarring.

Box car scars - Angular scars that usually occur on the temple and cheeks, and can be either superficial or deep, these are similar to chickenpox scars.

Rolling scars - Scars that give the skin a wave-like appearance.

Hypertrophic scars - Thickened, or keloid scars.

Pigmentation
Pigmented scars is a slightly misleading term as it suggests a change in the skin's pigmentation and that they are true scars; however, neither is true. Pigmented scars are usually the result of nodular or cystic acne (the painful 'bumps' lying under the skin). They often leave behind an inflamed red mark. Often, the pigmentation scars can be avoided simply by avoiding aggravation of the nodule or cyst. When sufferers try to 'pop' cysts or nodules, pigmentation scarring becomes significantly worse, and may even bruise the affected area. Pigmentation scars nearly always fade with time taking between 3 months to two years to do so, although rarely can persist.

On the other hand, some people—particularly those with naturally tanned skin—do develop brown hyperpigmentation scars due to increased production of the pigment melanin. These too typically fade over time.

Grading scale
There are multiple grading scales for grading the severity of acne vulgaris, three of these being: Leeds acne grading technique: Counts and categorises lesions into inflammatory and non-inflammatory (ranges from 0-10.0). 'Cook's acne grading scale: Uses photographs to grade severity from 0 to 8 (0 being the least severe and 8 being the most severe). Pillsbury scale: Simply classifies the severity of the acne from 1 (least severe) to 4 (most severe).