Acne Vulgaris

Acne Vulgaris – Causes, Symptoms, Classification and Treatment Options

Introduction and Classification

Acne is otherwise called as acne vulgaris. It is a chronic inflammatory disease. It occurs on the parts like: face, neck, upper chest, upper back, etc. According to studies, acne is the most prevalent disease in the world. It affects the patient both psychologically as well as psychosocially. The available topical treatments are having few side effects.

In order to avoid these side effects, researchers have formulated drug by incorporating nanotechnology in their formulation and they have also gone for combination therapy in order to decrease the concentration of the drug. In this article, we have discussed on acne, its pathophysiology, epidemiology, its treatment lines and finally the induction of acne in an animal model.

Acne: “Acme” is a Greek word of acne which means “Prime of life”. Acne is a chronic inflammatory state which occurs in the skin (Acne vulgaris). The inflammation of skin occurs due to the oil secreted by the sebaceous gland or which is otherwise called as oil glands of the skin.

Acne is seldom life-threatening condition, but it affects the self-esteem of an individual. People with the age group ranging from 12-24 are more prone to acne and about 85 % of the population are being affected

Grade I – Mild	Grade II – Moderate	Grade III and IV – Severe
·        Non-inflammatory ·        Few comedones	·        Mildly inflammatory ·        Several comedones ·        Few papules and pustules	·        Severely inflammatory ·        Several nodulocystic legions ·        Scarring

Acne Legion Classification

Here is how we can classify the types of legions found in Acne

Factors Responsible for Acne Formation

The actual process of Acne formation is complex and still not completely understood. From what is known as of now, we know there are few things which happen in parallel.

Hyperproliferation of the Follicular Epithelium: We do not understand what triggers this. The hyper keratinization occurs when there is cohesion between the follicle cells and when they do not shed properly on to the skin surface then it leads to the formation of micro-comedones which thereby results in occurrence of acne.

Excess Sebum Production due to Hormones: Sebum production plays an important role in the inflammation. The sebum production is controlled by the hormones namely androgen and testosterone. To begin with, androgen hormone is considered as an initial trigger. Men with severe acne have an increased level of dehydro-epiandrosterone sulfate (DHEAS) and a decreased level of sex hormone binding globulin (SHBG) responsible for elevating the androgen level. A drastically elevated level of androgen was found in women compared to men with acne. It has been found that the adult women with significant acne are having an abnormal DHEAS, androstenedione, and SHBG.

When sebum production increases due to hormones, and hyperproliferation of the follicular epithelium is present at the same time, excess cornified cells and sebum bind together and form an oily and greasy substance, which blocks and pores. Once the pores are blocked, this solution starts getting deposited under the skin forming comedones. These comedones can either be completely closed, in which case they appear white due to colour of the sebum and are called open comedones or whiteheads. Alternatively they can be open, allowing oxygen to come inside and oxidize the sebum and melanin present in the region turning the comedone darker. In this case they are called open comedones or blackheads

In addition, the sebum also serves as a medium for the growth of Propionibacterium acne which thereby leads to the formation of acne.

Role of Propionibacterium acne (P. acne): Propionibacterium is otherwise called as Cutibacterium, which is a gram-positive and anaerobic in nature responsible for inflammation of the skin. Under normal circumstances, P.acne is distributed all over the skin, but when blackheads and whiteheads form, the concentration of P.acne drastically increases in this region. This results into inflammatory response and papules, pustules, nodules and cysts get formed.

Other Factors Responsible for Acne Formation

• Medications:Medicines containing lithium and steroidal drugs.
• Due to the Cosmetics Used:Cosmetics containing greasy materials causes acne.
• Stress:A study in Singapore with the adolescents reveals that there is a correlation between the stress and acne severity.
• Hormonal Changes and Menstruation:At the time of puberty there will be an increased level of androgen hormone which in turn leads to sebum production.
• Hot and Humid Climatic Conditions:
• Type of Hair (Oily Hair): In case, if your hair is oily in nature then daily hair wash is necessary to prevent acne formation.
• Squeezing the Pimples:Sometimes people use to squeeze, pinch and pick their pimples, which may further worsen the condition and can live scars on their skin ⁴.
• Diet:In few studies, it has been observed that no food including chocolates has been recognized as an underlying factor. Even the relationship between the dietary dairy products and the acne is minor. In addition to this, the relationship between acne and diet remains unclear ⁵.
• Genetics:Acne occurs due to various genes like interleukin-1 alpha, CYP1A1
• Over Washing the Face with Cleansers:Hard scrubbing of the skin using cleansers.
• Environmental Factors: Which can be due to exposure to some chemicals or dust and even pollution can affect the skin.
• Due to other conditions like Pregnancy, polycystic ovary syndrome, and menopause.

Some Statistics About Acne

Acne occurs in areas of the body where the pore concentration is higher namely face, neck, chest, back and upper part of hands

People with white skin are more prone to acne compared to that of black skin. The reason for this is that the black skin is tough and they are less sensitive to sunlight whereas the opposite happens with white skin, they are more sensitive to sunlight and they are not having a tough skin as that of black skin.

Women are more prone to acne compared to men starting from their teens to middle age. This is because of various reasons like:

• More hormonal changes
• Women have more sensitive skin than men
• Skin is thinner in women as compared to men
• They use more cosmetic and beauty products and thus have a higher chance of blocked pores

Treatment Options for Acne

Most commonly used medication is topical creams and gels and they are used in case of mild and moderate acne. Whereas, the oral antibiotics are used in the case of severe acne vulgaris.

Before Treating acne there are Certain Factors to be considered:

• Type of acne and its severity.
• Type of skin (: oily skin or dry skin).
• Hyperandrogenism in women and their menstrual history.
• Past medical history.
• Acne stimulating medication.
• Presence of scarring.
• Patient’s age.

Acne treatments can be done using three different categories of topical / oral drugs They are as follows:

• Retinoids
• Antimicrobials
• Hormonal Therapy

Which of these method (or combination of them) should be used depends on the severity and type of acne. Hormonal therapy is used for female patients. While treating Acne vulgaris the medication should be capable of decreasing the inflammation, reducing the hyperproliferation of follicular epithelial cells and lower the production of sebum from the sebaceous gland. Along with these parameters, it should also be capable of preventing the acne scars.

From the above flowchart, we can say that for both the treatment (First line treatment and Alternative treatment) topical medication is given first in case of mild acne while coming to severe acne oral antibiotics are administered.

Topical Therapies for the Treatment of Acne

Topical therapy for treating acne includes both OTC (Over the counter) and prescription medicine.

• Acne vulgaris can be treated using a single topical therapy or a combination therapy along with other topical agents or in combination with oral antibiotics.
• The main objective of topical treatment is that the drug should be capable of penetrating into the skin (lipophilic environment).
• Various topical treatments (formulation) are available like topical gels, creams, lotions, face washes, solutions and ointments.
• The above entity is considered as a vehicle in which the drug is dispersed and administered. Vehicle plays a vital role in selecting the active ingredient or therapeutic agent. The activity of a therapeutic agent depends upon the vehicle because it has influence on the absorption of the drug through the skin. The vehicle selection depends on many parameters like type of skin (oily or dry in nature), the patient who is affected, affected area, and even depends on humidity and climatic conditions.
• Topical products can be directly administered to the affected area thereby increasing the exposure of drug to skin and reducing the systemic absorption of the drug.
• Despite being a good formulation in treating acne vulgaris, the topical medication may lead to some of the side effects like skin irritation and some other allergic reaction.
• Topical antibiotics are used in treating acne vulgaris because they have both anti-bacterial as well as anti-inflammatory property. The anti-bacterial property of antibiotics is essential in order to inhibit the bacterial protein synthesis and the anti-inflammatory property is essential in order to inhibit the chemotaxis of polymorphonuclear leukocytes. This is because the interleukin-8 (IL-8) is linked with the polymorphonuclear leukocytes (PMN) which in turn stimulates the keratinocyte proliferation.
• Topical treatment’s absorption depends on many factors like the amount or the quantity of medication applied, the surface area of the application, application time and its duration, time interval involved in the application, site of application, the thickness of stratum corneum and the selection of the vehicle

Topical Agents Involved in Acne Treatment

1. Topical Retinoids: Retinoids are otherwise called as comedolytics and they are obtained from vitamin A. It is used as monotherapy or in combination therapy along with other topical or oral antimicrobial agents. They also act as an anti-inflammatory agent as well as comedogenic activity.

The first line of treatment for patients having mild-moderate acne is topical retinoids. Topical retinoids create a harsh and difficult environment for acne instead of inhibiting them. In addition to these features, retinoid increases the penetration of other topical agents into the skin (pilosebaceous unit). The main aim of topical retinoids includes:

• Inhibition of the keratinocyte proliferation.
• Increase in the turnover of follicular epithelial cells.
• Reducing or suppressing the formation of microcomedones.

Topical retinoids used in acne treatment can be classified in the following manner.

• Tretinoin (Cream, gel or microsphere gel vehicle).
• Isotretinoin
• Adapalene (Cream, gel, lotions).
• Tazarotene (Cream, gel or foam).

Multiple pathogenic features including the inflammatory and non-inflammatory lesions can be targeted by administering topical retinoids along with other anti-microbial agents

Tretinoin: It has been used for the past three decades in the treatment of acne. Tretinoin is a derivative of vitamin A. It is a comedolytic agent which is helpful in treating acne. It has an anti-inflammatory property and prevents the blockage of the pilosebaceous unit.

• Tretinoin is present in the form of cream, gel, and liquid.
• Tretinoin is inactivated by benzoyl peroxide when they are administered together. In order to avoid the oxidation and inactivation of tretinoin by benzoyl peroxide, they are given in the alternative timing. Example tretinoin is given at night time and benzoyl peroxide is given in the morning time.

The side effect of using tretinoin includes:

• Dryness in the skin
• Peeling of the skin
• Irritation in the skin
• Leads to redness of the skin
• Photosensitivity
• Burning sense
• Contraindicated during pregnancy

However, these side effects can be reduced by application of a suitable quantity of medication, the frequency of application, by avoiding exposure to sunlight, using protective clothing and hats and also by applying suitable sunscreen with a sun protection factor (SPF) greater than 15.

Isotretinoin (topical): Isotretinoin undergoes an isomerization to tretinoin. Isotretinoin has a similar efficacy as that of tretinoin. When we compare adapalene and isotretinoin, it is said that the isotretinoin is having an increased effect compared to adapalene. Isotretinoin lowers inflammatory as well as non-inflammatory lesions. When isotretinoin is combined with erythromycin, it shows better activity compared to isotretinoin alone.

Adapalene: Adapalene is used as the first line treatment in the acne vulgaris. It is known as a synthetic retinoid compound. It has an anti-inflammatory property which acts on acne lesions. The differentiation in the follicular epithelial cells is normalized.

• They are less effective as compared to other retinoids. But, adapalene is having less irritation compared to other topical retinoids and in addition to this, there is no photosensitivity.
• It is more lipophilic in nature, which allows it to penetrate more rapidly into the skin.
• Studies revealed that a concentration of 0.1% of adapalene and 0.025% of tretinoin are having similar efficacy, but adapalene has much less irritation and side effects and hence is preferred.
• When adapalene is combined with benzoyl peroxide, it is having more activity.
• Combination of 0.1% adapalene and 1% clindamycin has better activity than using both the drugs individually.
• In order to attain a follicular targeting, the adapalene is integrated with the microcrystals (with a size range of 3-10 µm).

Tazarotene: Tazarotene which is marketed as TAZORAC is a synthetic retinoid with a comedolytic property (causes lysis of comedones in acne). It is used in the treatment of mild to moderate acne.

• Commercially, it is available as a gel (0.05 %, 0.1%) which is applied daily in the evening only once.
• They are having more activity as compared to tretinoin (0.025% and 0.05%).
• Increased efficacy is found by combining tazarotene and clindamycin together.
• Better efficacy is observed when using a triple preparation (tazarotene 0.1% gel, clindamycin 1%/Benzoyl peroxide 5% gel and erythromycin/Benzoyl peroxide).

Tazarotene is a pro-drug which gets converted into tazarotenic acid in the keratinocytes. Tazarotene acts as an anti-inflammatory agent. It is considered a second-line treatment. Since, this drug causes skin irritation and dryness, they are administered only when there is no response to adapalene and tretinoin.  

2. Benzoyl Peroxide (BP): BP is available as cream, gel, and lotion and it possesses anti-microbial, anti-inflammatory and comedolytic property. It is employed as a peeling agent in the treatment of acne.

• Used in treating the inflammatory acne like papule, pustules, and cysts. The presence of oil on the skin is reduced as well as the size of the sebaceous gland is decreased.
• BP is lipophilic in nature which allows it to enter into the stratum corneum and easily penetrate into the pilosebaceous unit.
• In order to obtain a better efficacy, BP is combined with clindamycin⁹. Benzoyl peroxide rapidly degraded into benzoic acid and hydrogen peroxide and degrades the bacterial protein by releasing the free radical oxygen against the acnes.
• It is used as a monotherapy in mild to moderate acne. In order to decrease the resistance of the acnesspecies and to improve the efficacy, BP is combined with topical antibiotics.
• BP is available in various concentrations like 2.5%, 5% and 10% comprising of lotion, creams, and gels. It is also available as topical washes, foams, and also used as a leave on or wash-off agents.
• The side effects of BP comprise of dryness, burning sensation, erythema, peeling, itchiness and sometimes bleaching of the clothing and skin.

3. Azelaic Acid: It is a natural dicarboxylic acid which leads to inhibition of acne protein synthesis. It has several properties like anti-inflammatory, antioxidant, anti-keratinizing properties and bacteriostatic.

• After application of azelaic acid, the concentration Propionibacterium acne is reduced on the surface of the skin.
• Azelaic acid inhibits the pro-inflammatory cytokines thereby reducing the inflammation.
• It also causes the induction of peroxisome proliferator – which decreases the inflammatory responses.
• Azelaic acid is marketed as gels and creams for topical application. Since, these formulations contain a high quantity of azelaic acid; it leads to many side effects like burning, irritation, stinging and redness of the skin.
• In order to overcome these side effects, lamellar liquid crystal (LLC) system containing azelaic acid is prepared with a smaller quantity of azelaic acid for topical application.

4. Topical Antibiotics: Topical antibiotics mainly focus on the Propionibacterium acne.

• Clindamycin and erythromycin are usually used as a topical application for treating acne. Clindamycin and tetracyclines are possessing bacteriostatic activity.
• Quinolone scaffold exhibits its bactericidal activity by interacting with the DNA supercoiling.
• Dapsone is considered as an anti-inflammatory agent as well as an antibiotic agent. It inhibits the bacterial DNA synthesis. It has been stated that the dapsone is safe and effective for treating long-term acne.
• Side effects of dapsone include mild irritation and dryness of skin. The orange-brown coloration of the skin occurs when dapsone and Benzoyl peroxide is administered together due to oxidation of dapsone.
• Studies show that after a certain period of time bacterial resistance develops while using the topical antibiotic as an only treatment. So, in order to avoid the bacterial resistance, the topical antibiotics can be administered along with the benzoyl peroxide or any other suitable topical agents like retinoids.
• Studies address that the frequency of topical antibiotic monotherapy for treating acne has decreased when comparing the combined treatment of topical antibiotic with Benzoyl peroxide.

Oral Antibiotics and Isotretinoin

Oral Antibiotics: The oral antibiotics are used in the treatment of moderate to severe acne and also the acne which is resistant to topical therapies. Oral antibiotics are for long-term use. These compounds express their activity by inhibiting the Propionibacterium acnes and the formation of the inflammatory mediators.

Tetracycline, doxycycline, minocycline, erythromycin, and azithromycin are used as a choice of systemic antibiotics in the treatment of acne. However, there are certain side effects of erythromycin and tetracycline like photo-sensitivity, vulvovaginal candidiasis, and gastrointestinal irritation. In addition, to this tetracycline has got another side effect like permanent bone and tooth pigmentation.

List of oral antibiotics used to treat acne:

Tetracyclines:

Tetracycline – Duration of 4-6 month. Side effects including gastro-intestinal upset and photosensitivity.

Doxycycline – Duration of 4-6 month. Side effects including gastro-intestinal upset and photosensitivity.

Minocycline – Duration of 4-6 months. Side effects including vertigo and hyper-pigmentation of the skin.

Macrolides:

Erythromycin- Duration of 4-6 months. Side effects including gastro-intestinal upset and vaginal candidiasis.

Oral Isotretinoin: It has been used in treating acne by exhibiting its action against multiple factors like decreasing sebum secretion, the formation of comedeons, colonization of skin with Propionibacterium acnes. They also exhibit anti-inflammatory activity.

Initially, the treatment is started with a low dose and subsequently increased based on the tolerability. When the drug is administered along with the food, its bioavailability is increased.

There are also a number of side effects associated with systemic isotretinoin therapy like teratogenicity, dryness of skin, lips, nasal passages and eye. But, most of the side effects can be tolerated and treated.

In case, if any problem occurs during oral isotretinoin therapy, then immediately it should be reported to physician and laboratory monitoring is required during the treatment. Suggested tests comprise of blood count, low-density lipoprotein, high- density lipoprotein, liver enzymes, triglycerides, total cholesterol level during fasting condition.

Hormonal Therapies

Acne can be effectively treated with hormonal treatments. In this treatment, the androgen level has been lowered and their effect on the sebaceous gland has also been opposed.

Anti-androgens or androgen receptor blocker, agents in the ovary or adrenal gland which is responsible for decreasing the production (endogenous) of androgens such as estrogens, a combination of oral contraceptives, gonadotropin-releasing hormone agonists are used in hormonal therapies for the treatment of acne.

Summary of the Recommended Medication

Medication	Type	Concentration	Dosage	Comments
Tretinoin	Topical	0.025% gel	Topically apply to cover affected area	Cannot be used with Benzoyl Peroxide
Adapalene	Topical	0.1% gel	Topically apply to cover affected area
Tazarotene	Topical	0.05%, 0.1%	Topically apply to cover affected area
Benzoyl Peroxide	Topical	2.5%, 5% & 10%	Topically apply to cover affected area	Cannot be used with tretinoin
Tetracycline	Oral	250 – 500 mg	Twice a day Use for 4-6 months and then assess	Should be used with Benzoyl Peroxide to avoid development of drug resistance Contraindicated in pregnant women and children below 9 yrs of age
Doxycycline	Oral	100 – 200 mg	Twice a day Use for 4-6 months and then assess	Should be used with Benzoyl Peroxide to avoid development of drug resistance Contraindicated in pregnant women and children below 9 yrs of age
Minocycline	Oral	50 – 200 mg	Twice a day Use for 4-6 months and then assess	Should be used with Benzoyl Peroxide to avoid development of drug resistance Contraindicated in pregnant women and children below 9 yrs of age
Erythromycin	Oral	500 mg	Twice a day Use for 4-6 months and then assess	Should be used with Benzoyl Peroxide to avoid development of drug resistance Can be used in pregnant women and children
Trimethoprim/ sulfamethoxazole	Oral	80/400 mg or 160/800 mg	Four times a day Use for 4-6 months and then assess	Useful in patients who are resistant to other antibiotics
Isotretinoin	Oral	Can start with 20 mg per day After 6 weeks patient will start to see improvement. After 10 months to 24 months, patients will be completely cured	Actual guideline is to start with 0.5 mg/kg and increase up to 1 mg/kg as tolerated by the patient. Stop after a cumulative dosage of 120 – 150 mg/kg. Overall dosage duration can be 20-22 weeks	Depression can be one of the side effects. Worst side effect is teratogenesis. This can cause permanent deformities in the fetus if the woman is pregnant. Hence before starting isotretinoin, pregnancy test is a must. During the usage pregnancy test should be done every month. Contraceptives need to be taken regularly during the treatment Women cannot conceive 6 months after the dosage stops Men cannot plan family 3 months after the dosage stops Blood donation is not allowed 6 months after the dosage stops