Acne also is known as acne vulgaris is a long-term skin disease that occurs when hair follicles are clogged with dead skin cells and oil from the skin. It is characterized by blackheads or whiteheads, pimples, oily skin, and possible scarring. It primarily affects areas of the skin with a relatively high number of oil glands, including the face, upper part of the chest, and back. The resulting appearance can lead to anxiety, reduced self-esteem and, in extreme cases, depression or thoughts of suicide.
Acne vulgaris is one of the commonest skin disorders which dermatologists have to treat, mainly affect adolescents, though it may present at any age. Acne by definition is a multifactorial chronic inflammatory disease of pilosebaceous units.[rx] Various clinical presentations include seborrhoea, comedones, erythematous papules, and pustules, less frequently nodules, deep pustules or pseudocysts, and ultimate scarring in few of them. Acne has four main pathogenetic mechanism—increased sebum productions, follicular hyperkeratinization, Propionibacterium acne (P. acne) colonization, and the products of inflammation.[rx–rx]
Types of Acne
The following types are possible:
- Whiteheads – These remain under the skin and are small
- Blackheads – Clearly visible, they are black and appear on the surface of the skin
- Papules – Small, usually pink bumps, these are visible on the surface of the skin
- Pustules – Clearly visible on the surface of the skin. They are red at their base and have pus at the top
- Nobles – Clearly visible on the surface of the skin. They are large, solid, painful pimples that are embedded deep in the skin
- Cysts – Clearly visible on the surface of the skin. They are painful and filled with pus. Cysts can cause scars.
Grading the severity of acne[rx]
| Grade | Severity | Clinical findings |
|---|---|---|
| I | Mild | Open and closed comedones with few inflammatory papules and pustules |
| II | Moderate | Papules and pustules, mainly on face |
| III | Moderately severe | Numerous papules and pustules, and occasional inflamed nodules, also on chest and back |
| IV | Severe | Many large, painful nodules and pustules |
Causes of Acne
Genes
- The predisposition to acne for specific individuals is likely explained by a genetic component, a theory which is supported by studies examining the rates of acne among twins and first-degree relatives. Severe acne may be associated with XYY syndrome. Acne susceptibility is likely due to the influence of multiple genes, as the disease does not follow a classic (Mendelian) inheritance pattern.
- Multiple gene candidates have been proposed including certain variations in tumor necrosis factor-alpha (TNF-alpha), IL-1 alpha, and CYP1A1 genes, among others. The increased risk is associated with the 308 G/A single nucleotide polymorphism variation in the gene for TNF.
Hormones
- Hormonal activity, such as occurs during menstrual cycles and puberty, may contribute to the formation of acne. During puberty, an increase in sex hormones called androgens causes the skin follicle glands to grow larger and make more oily sebum.
- Several hormones have been linked to acne, including the androgens testosterone, dihydrotestosterone (DHT), and dehydroepiandrosterone (DHEA); high levels of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) have also been associated with worsened acne.
- Both androgens and IGF-1 seem to be essential for acne to occur, as acne does not develop in individuals with complete androgen insensitivity syndrome (CAIS) or Laron syndrome (insensitivity to GH, resulting in very low IGF-1 levels).
Infections
- It is widely suspected that the anaerobic bacterial species Propionibacterium acnes (P. acnes) contributes to the development of acne, but its exact role is not well understood.[rx] There are specific sub-strains of P. acnes associated with normal skin and moderate or severe inflammatory acne.
Stress
- Few high-quality studies have been performed which demonstrate that stress causes or worsens acne. While the connection between acne and stress has been debated, some research indicates that increased severity is associated with high-stress levels in certain contexts such as hormonal changes seen in premenstrual syndrome.
Environmental factors
- Mechanical obstruction of skin follicles with helmets or chinstraps can worsen pre-existing acne.
Diet
- The relationship between diet and acne is unclear, as there is no high-quality evidence that establishes any definitive link between them. High-glycemic-load diets have been found to have different degrees of effect on acne severity.
- Multiple randomized controlled trials and nonrandomized studies have found a lower-glycemic-load diet to be effective in reducing acne. There is weak observational evidence suggesting that dairy milk consumption is positively associated with a higher frequency and severity of acne. Milk contains whey protein and hormones such as bovine IGF-1 and precursors of dihydrotestosterone.
Symptoms of Acne
- The severity of acne can vary quite a bit. Doctors distinguish between mild, moderate and severe forms of acne. There are also inflammatory and non-inflammatory types of acne. Non-inflammatory acne is a milder type, which most people would refer to as “pimples” or “blackheads” rather than “acne.”
- Unlike normal pimples – acne develops over a longer period of time and stays longer. It sometimes leaves small red marks or scars behind. “Normal” pimples usually form quickly and then go away again soon afterward.
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Mild acne – People with mild acne have comedones (blackheads or whiteheads). These are clogged pores in the skin. The dark color of blackheads has nothing to do with dirt: They look dark because this kind of blackhead is “open” and the skin pigment melanin reacts with oxygen in the air. Whiteheads are closed and have a white or yellowish head. The more oil builds up, the more likely it is that bacteria will multiply and lead to inflammatory acne. Acne is also considered to be “mild acne” if someone only has a few pimples, or only has small ones.
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Moderate acne – People who have moderate acne have noticeably more pimples. Inflamed pimples are called “papules” (small bumps) or “pustules” (filled with yellow pus).
-
Severe acne – People who have severe forms of acne have a lot of papules and pustules, as well as nodules on their skin. These nodules are often reddish and painful. The acne may lead to scarring.
Stage
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Grade 1: Comedones. They are of two types, open and closed. Open comedones are due to plugging of the pilosebaceous orifice by sebum on the skin surface. Closed comedones are due to keratin and sebum plugging the pilosebaceous orifice below the skin surface.
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Grade 2: Inflammatory lesions present as a small papule with erythema.
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Grade 3: Pustules.
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Grade 4: Many pustules coalesce to form nodules and cysts.
Acne can leave various scars after healing, which may present as depressed scars or hypertrophic and keloidal scars. Depressed scars may be gentle contour (boxcar scars) or ice pick scars, which are deep pits. Acne is associated with seborrhoea and in the case of hyperandrogenism associated with hirsutism, acanthosis nigricans, irregular menstrual period, and weight gain
Differential Diagnosis of Acne Vulgaris
| Disease/condition | Differentiating characteristics |
|---|---|
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Often seen in black patients; lesions localized to the posterior neck; initially, papules and pustules that may progress to confluent keloids |
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Secondary to systemic medications, topical corticosteroid medications, contrast dye, and cosmetic products; may be abrupt in onset and correlation with exposure; improvement with cessation of exposure, |
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Comedones, pustules, and cysts that localize to the post-auricular area, axillae, and groin; history of exposure to halogenated aromatic hydrocarbons; the patient may have other systemic manifestations |
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Open and closed comedones on periorbital and malar areas; no inflammatory lesions; patients are usually older with a history of significant sun exposure |
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Erythematous papules and pustules that are follicularly-based; often affects trunk and extremities |
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Frequently occurs in patients with acne who have been on long-term antibiotic medications; pustules and nodules; may also occur in HIV + patients, and after hot tub exposure; lesions may be cultured if acneiform lesions do not respond to the typical antibiotic regimen |
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Yellow/brown/red smooth papules in the periorbital and eyelid skin; biopsy shows caseating epithelioid granulomas |
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White keratinaceous cysts; lesions are usually persistent; noninflammatory |
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Papules and pustules in the periorificial distribution; often exacerbated by topical corticosteroid use |
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Rapid onset of erythema, abscesses, cysts, and possible sinus tracts, no comedones |
|
Various forms; background erythema with inflammatory papules and pustules often superimposed; environmental factors often can trigger |
|
Noninflammatory papules that typically localize to the eyelids and malar cheeks; skin biopsy test results show dilated cysts with tadpole appearance |
|
Small waxy papules over the medial cheeks, nose, and forehead; multiple lesions associated with tuberous sclerosis; skin biopsy test results show dermal fibrosis and vascular proliferation and dilatation (angiofibromas). Facial angiofibromas are also a feature of multiple endocrine neoplasia type I and, rarely, Birt-Hogg-Dubé syndrome. |
Causative agents of drug-induced acneiform eruptions
| Class of agent | Examples |
|---|---|
|
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| Corticosteroids and corticotropin | |
| Androgens and anabolic Steroid medications | |
| Hormonal contraceptive medications | |
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| Tricyclic antidepressant medications | |
| Lithium | |
| Antiepileptic drugs | |
| Aripiprazole | |
| Selective serotonin reuptake inhibitors | |
|
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| Vitamins B1, B6, and B12 | |
|
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| Dactinomycin (actinomycin D) | |
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| Cyclosporine | |
| Sirolimus | |
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| Isoniazid | |
| Rifampin | |
| Ethionamide | |
|
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| Iodine | |
| Bromine | |
| Chlorine | |
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| Epidermal growth factor receptor inhibitors | |
| Multitargeted tyrosine kinase inhibitors | |
| Vascular endothelial growth factor inhibitor | |
| Proteasome inhibitor | |
| Tumor necrosis factor alfa inhibitors | |
| Histone deacetylase inhibitor |
Treatment
- Salicylic acid – It has been used for many years in acne as a comedolytic agent, but is less potent than topical retinoid.[rx]
- Azelaic acid – It is available as 10–20% topical cream which has been shown to be effective in inflammatory and comedonal acne.[rx,rx]
- Lactic acid/Lactate lotion – It is found to be helpful in preventing and reduction of acne lesion counts.[rx]
- Tea tree oil 5% – Initial clinical response with this preparation is inevitably slower compared to other treatment modalities.[rx]
- Picolinic acid gel 10% – It is an intermediate metabolite of the amino acid, tryptophan. It has antiviral, antibacterial, and immunomodulatory properties. When applied twice daily for 12 weeks found to be effective in both type of acne lesions, but further trials are needed to confirm its safety and efficacy.[rx]
- Dapsone gel 5% – It is a sulfone with anti-inflammatory and antimicrobial properties. The trials have confirmed that topical dapsone gel 5% is effective and safe as monotherapy and in combination with other topical agents in mild-to-moderate acne vulgaris.[rx]
- Benzoyl peroxide – The common acne vulgaris treatment benzoyl peroxide cream. Benzoyl peroxide (BPO) is the first-line treatment for mild and moderate acne due to its effectiveness and mild side-effects (mainly skin irritation). In the skin follicle, benzoyl peroxide kills P. acnes by oxidizing its proteins through the formation of oxygen free radicals and benzoic acid. These free radicals are thought to interfere with the bacterium’s metabolism and ability to make proteins. Additionally, benzoyl peroxide is mildly effective at breaking down comedones and inhibiting inflammation. Benzoyl peroxide may be paired with a topical antibiotic or retinoid such as benzoyl peroxide/clindamycin and benzoyl peroxide/adapalene, respectively.
- Retinoids – Retinoids are medications which reduce inflammation, normalize the follicle cell life cycle, and reduce sebum production. They are structurally related to vitamin A. The retinoids appear to influence the cell life cycle in the follicle lining. This helps prevent the accumulation of skin cells within the hair follicle that can create a blockage. They are a first-line acne treatment, especially for people with dark-colored skin, and are known to lead to faster improvement of postinflammatory hyperpigmentation.
- Frequently used topical retinoids include adapalene, isotretinoin, retinol, tazarotene, and tretinoin. They often cause an initial flare-up of acne and facial flushing and can cause significant skin irritation.
Topical Therapy
-
Topical retinoids like retinoic acid, adapalene, and tretinoin are used alone or with other topical antibiotics or benzoyl peroxide. Retinoic acid is the best comedolytic agent, available as 0.025%, 0.05%, 0.1% cream, and gel.[8]
-
Topical clindamycin 1% to 2%, nadifloxacin 1%, and azithromycin 1% gel and lotion are available. Estrogen is used for Grade 2 to Grade 4 acne.
-
Topical benzoyl peroxide is now available in combination with adapalene, which serves as comedolytic as well as antibiotic preparation. It is used as 2.5%, 4%,and 5% concentration in gel base.[9]
-
Azelaic acid is antimicrobial and comedolytic available 15% or 20% gel. It can also be used in postinflammatory pigmentation of acne.
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Beta hydroxy acids like salicylic acid are used as topical gel 2% or chemical peel from 10% to 20% for seborrhoea and comedonal acne, as well as, pigmentation after healing of acne.
-
Topical dapsone is used for both comedonal and papular acne, though there are some concerns with G6PD deficient individuals.
Systemic Therapy
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Doxycycline 100 mg twice a day as an antibiotic and anti-inflammatory drug as it affects free fatty acids secretion and thus controls inflammation.
-
Minocycline 50 mg and 100 mg capsules are used as once a day dose.
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Other antibiotics such as amoxicillin, erythromycin, and trimethoprim/sulfamethoxazole are sometimes used, and if bacterial overgrowth or infection is masquerading as acne, other antibiotics such as ciprofloxacin may be used in pseudomonas related ‘acne.’
-
Isotretinoin is used as 0.5 mg/kg to 1 mg/kg body weight in daily or weekly pulse regimen. It controls sebum production, regulates pilosebaceous epidermal hyperproliferation, and reduces inflammation by controlling P. acnes. It may give rise to dryness, hairless, and cheilitis.
-
An oral contraceptive containing low dose estrogen 20 mcg along with cyproterone acetate as anti-androgens are used for severe recurrent acne.
-
Spironolactone (25 mg per day) can also be used in males. It decreases the production of androgens and blocks the actions of testosterone. If given to females, then pregnancy should be avoided because the drug can cause feminization of the fetus.[10]
Antibiotics
| Antibiotic, dose | Notes |
|---|---|
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Antibiotics are frequently applied to the skin or taken orally to treat acne and are thought to work due to their antimicrobial activity against P. acnes and their ability to reduce inflammation. With the widespread use of antibiotics for acne and an increased frequency of antibiotic-resistant P. acnes worldwide, antibiotics are becoming less effective, especially macrolide antibiotics such as topical erythromycin. Commonly used antibiotics, either applied to the skin or taken orally, include clindamycin, erythromycin, metronidazole, sulfacetamide, and tetracyclines such as doxycycline and minocycline.
Hormonal agents
- In women, acne can be improved with the use of any combined birth control pill. These decrease the production of androgen hormones by the ovaries, resulting in lower skin production of sebum, and consequently reduce acne severity.
- Hormonal therapies should not be used to treat acne during pregnancy or lactation as they have been associated with birth disorders such as hypospadias, and feminization of the male fetus or infant. Finasteride is likely an effective treatment for acne.
Azelaic acid
- Azelaic acid has been shown to be effective for mild to moderate acne when applied topically at a 20% concentration. Treatment twice daily for six months is necessary, and is as effective as topical benzoyl peroxide 5%, isotretinoin 0.05%, and erythromycin 2%. Azelaic acid is thought to be an effective acne treatment due to its ability to reduce skin cell accumulation in the follicle, and its antibacterial and anti-inflammatory properties.
Salicylic acid
- Salicylic acid is a topically applied beta-hydroxy acid that stops bacteria from reproducing and has keratolytic properties. It opens obstructed skin pores and promotes shedding of epithelial skin cells. Salicylic acid is known to be less effective than retinoid therapy. Dry skin is the most commonly seen side effect with topical application, though darkening of the skin has been observed in individuals with darker skin types.
Oral contraceptives
- Estrogen is commonly combined with progestin to avoid the risk of endometrial cancer. Anti-acne effect of oral contraceptive governed by decreasing level of circulatory androgens through inhibition of luteinizing hormones (LH) and follicle stimulating hormone (FSH).[rx,rx] The current FDA approved agents include norgestimate with ethinyl estradiol and norethindrone acetate with ethinyl estradiol.
Spironolactone
Cyproterone acetate
- It is the first androgen receptor blocking agent to be well studied and found to effective in acne in females.[rx,rx] Higher doses have been found to be more effective than the lower dose. It is also combined (2 mg) with ethinyl estradiol (35 or 50 μg) as an oral contraceptive formulation to treat acne.
Oral isotretinoin
- Oral retinoid is indicated in severe, moderate-to-severe acne or lesser degree of acne producing physical or psychological scarring, unresponsive to adequate conventional therapy.[rx,rx] It is the only drug that affects all four pathogenic factors implicated in the etiology of acne.
- Although there are many studies, very large evidence-based study is lacking to confirm the dosing schedule. The approved dose is 0.5–2 mg/kg/day, which is usually given for 20 weeks.[rx–rx] Alternatively, a lower dose can be used for a longer period, with a total cumulative dose of 120 mg/kg.[rx] New developments and future trends are low-dose long-term isotretinoin regimens and new isotretinoin formulations (micronized isotretinoin).[rx]
Combined Therapy
- Combined agents such as erythromycin/zinc, erythromycin/tretinoin, erythromycin/isotretinoin, erythromycin/benzoyl peroxide, and clindamycin/benzoyl peroxide are increasingly being used and are useful in reducing the development of antibacterial resistance in P acnes.
- Most of these topical preparations are available in a variety of strengths and delivery systems. Drying agents (gels, washes, and solutions) are particularly suited to oily skin, whereas creams, lotions, and ointments are more suited to patients with dry, easily irritated skin.[rx]
Physical Treatment
Comedones
- Both open and closed comedones can be removed mechanically with comedone extractor and a fine needle or a pointed blade.[rx] The pre-procedure topical retinoid application makes the procedure easier. Gentle cautery and laser puncture of macrocomedones are also useful procedure.[rx] The limitations of comedo extraction include incomplete extraction, refilling, and the risk of tissue damage. Active deep inflammatory lesions
Phototherapy
Visible light
- They are indicated for mild-to-moderate inflammatory acne. In vitro and in vivo exposure of acne bacteria to 405–420 nm of ultraviolet free blue light results in the photo-destruction through the effect on the porphyrin produced naturally by P. acne.[rx] Use of limited spectrum wavelength, such as blue light (peak at 415 nm), and mixed blue and red light (peak at 415 and 660 nm) have been found to be effective in reducing acne lesions after 4–12 weeks.[rx,]
Photodynamic therapy
Physical treatment of scars
- Acne scar can be broadly divided into two groups, those involving tissue losses (Ice pick scar, Box scar, Rolling scar, and Follicular macular atrophy) and those involving tissue excess (hypertrophic scars or keloids). Currently available treatment for scars include simple excision, and suturing, either alone or combined with punch grafting and laser resurfacing, dermabrasion, various type of lasers, chemical peels, and fillers.
- For hypertrophic scars, treatment includes pressure therapy, IL corticosteroid, 5-fluorouracil and bleomycin injections, surgical excision, radiotherapy, laser therapy and cryotherapy. All the procedures have their own merits and demerits; to be chosen carefully seeing the merit.[rx–rx]
Acne and diet
- Dietary restriction has not been demonstrated to be a benefit in the treatment of acne.[rx,rx] The myth that diet affects acne is widespread, but previous studies are not supporting it. Of late, various authors again claiming that there is the definite role of diet in acne but to conclude that further controlled trials are needed.[rx–rx]
- It has been shown that the prevalence of acne is lower in rural, nonindustrialized societies than in modernized western populations may be due to lower glycemic index diet, claims one trial.[rx] Although not currently recognized within our dermatology standard of care, but due to “consistent and good quality patient-oriented evidence”, dietary management of acne appears to be accumulating. The benefit of dietary management in the treatment of acne has been neither demonstrated nor disproved.[rx,rx]
Other medications
Hydroquinone lightens the skin when applied topically by inhibiting tyrosinase, the enzyme responsible for converting the amino acid tyrosine to the skin pigment melanin, and is used to treat acne-associated postinflammatory hyperpigmentation. By interfering with new production of melanin in the epidermis, hydroquinone leads to less hyperpigmentation as darkened skin cells are naturally shed over time. Improvement in skin hyperpigmentation is typically seen within six months when used twice daily.
- Lasers and photodynamic therapy. A variety of light-based therapies have been tried with some success. But further study is needed to determine the ideal method, light source and dose.
- Chemical peel. This procedure uses repeated applications of a chemical solution, such as salicylic acid, glycolic acid or retinoic acid. Any improvement in acne is not long lasting, so repeat treatments are usually needed.
- Extraction of whiteheads and blackheads. Your doctor may use special tools to gently remove whiteheads and blackheads (comedos) that haven’t cleared up with topical medications. This technique may cause scarring.
- Steroid injection. Nodular and cystic lesions can be treated by injecting a steroid drug directly into them. This therapy has resulted in rapid improvement and decreased pain. Side effects may include thinning in the treated area.
- Resorcinol: helps break down blackheads and whiteheads
- Benzoyl peroxide: kills bacteria, accelerates the replacement of skin, and slows the production of sebum
- Salicylic acid: assists the breakdown of blackheads and whiteheads and helps reduce inflammation and swelling
- Sulfur: exactly how this works is unknown
- Retin-A: helps unblock pores through cell turnover
- Azelaic acid: strengthens cells that line the follicles, stops sebum eruptions, and reduces bacterial growth. There is cream for acne, but other forms are used for rosace
Therapy
Various topical and systemic drugs are available to treat acne, which may sometimes confuse the treating dermatologist. To overcome this situation a panel of physicians and researchers worked together as a “Global Alliance” and “Task Force” to improve outcomes in acne treatment.[rx–rx] They have tried to give consensus recommendation for the treatment of acne, mostly evidence-based and inputs from various countries. The similar alliance has also been formed in India recently with their recommendations.[rx]
Topical retinoid
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It should be the primary treatment for most forms of acne vulgaris.
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To be applied to the entire affected area.
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Antimicrobial to be added for inflammatory lesions.
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An essential part of maintenance therapy.
Combination therapy
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It works better and clearing of the lesion is faster.
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Stop antibiotic if inflammatory lesion subsides.
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If withdrawal is not possible, switch to benzoyl peroxide plus an antibiotic.
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Topical retinoid can be continued to prevent remission.
Antibiotics
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Oral and topical antibiotics not to be used as monotherapy to prevent bacterial resistance.
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Helpful in moderate-to-severe acne.
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Generally, oral antibiotics are well tolerated, sometimes associated with severe adverse events.
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Always use the same antibiotic if it was effective previously.
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Doxycycline and minocycline are more effective than tetracycline.
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Do not use chemically dissimilar oral and topical antibiotic together.
Hormonal therapy
- It is an excellent choice in women requiring oral contraceptive (estrogen-containing) for other reason and having moderate-to-severe acne with SAHA symptoms. Oral antiandrogen like spironolactone and cyproterone acetate can be useful in the treatment of acne.
Oral isotretinoin
- It is approved in severe recalcitrant nodulocystic acne. It can also be used in moderate-to-severe acne vulgaris resistant to conventional therapy, frequently relapsing, with severe psychological and physical scarring due to acne. Pre-treatment ccounseling patient selection, and monitoring are critical due to its side effects like teratogenicity, and adverse psychiatric events.
Approach to therapy for acne vulgaris[rx]
| Severity; clinical findings | Treatment options | |
|---|---|---|
| First line | Second line | |
| Mild | ||
| Comedonal | Topical retinoid | Alternative topical retinoid Salicylic acid washes |
| Papular/pustular | Topical retinoid Topical antimicrobial
Combination products |
Alternative topical retinoid plus alternative topical antimicrobial Salicylic acid washes |
| Moderate | ||
| Papular/pustular | Oral antibiotics
Topical retinoid ± benzoyl peroxide |
Alternative oral antibiotic Alternative topical retinoid Benzoyl peroxide |
| Nodular | Oral antibiotic Topical retinoid ± benzoyl peroxide |
Oral isotretinoin Alternative oral antibiotic Alternative topical retinoid Benzoyl peroxide |
| Severe | Oral isotretinoin | High-dose oral antibiotic Topical retinoid (also maintenance therapy) Benzoyl peroxide |
References
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