Acne Vulgaris: Pathophysiology, diagnosis, and treatment of a common dermatologic condition

Acne Vulgaris: Pathophysiology, diagnosis, and treatment of a common dermatologic condition Dr. Mohamed Emam Lecturer in Clinical Pharmacy Department Faculty of Pharmacy Beni Suef University

Hair Pilosebaceous unit = hair + hair follicle + sebaceous gland

What is Acne? Acne vulgaris is a chronic, inflammatory disorder of the pilosebaceous units of the skin. Sebaceous gland found in hair-covered areas Functions to secrete sebum which is an oily substance that acts to protect and waterproof skin and hair and keep it from being dry, brittle, and cracked

Epidemiology Age Acne can present at any point during a person s life but 85% is between 12-24 years old Adolescent acne usually presents prior to the onset of puberty Sex During adolescence, acne is more common in males than females During adulthood, acne is more common in females than males

Psychosocial impact Social, psychological and emotional impairment Patients are prone to depression, social withdrawal, anxiety and anger Scarring associated with acne can lead to lifelong problems with regards to self confidence

Pathophysiology Primary Causes Increased sebum production Abnormal epithelial desquamation Bacterial growth Inflammation Secondary Triggers Mechanical obstruction (e.g., helmets, shirt collars) Increased hormonal activity (e.g., menstrual cycles, puberty) Stress (due to increased output of hormones from the adrenal gland) Cosmetics and emollients (occlude follicles and cause an acneiform eruption) Medications with halogens (iodine, chlorine, bromine), Lithium, barbiturates, androgens, topical coal tar, phenytoin Anabolic steroids Diet (no proven effect but patient should eat well balanced diet and excess fat and carbohydrate should be avoided)

1. Increased Sebum Production Maturation of the adrenal gland or an increase in the number of cells of the sebaceous gland can lead to excess sebum production Caused mainly by androgens in both sexes e.g. testosterone which is converted to Dihydrotestosterone (DHT) DHT increase size and activity of sebaceous gland resulting in increase in sebum

2. Abnormal Epithelial Desquamation Abnormal clumping of horny cells in pilosebaceous unit Hyperkeratinization of the hair follicle prevents the normal shedding of follicular keratinocytes This results in follicular canal widening and increased cell production Sebum mixes with excess loose cells in the follicular canal to form a keratinous plug, or microcomedo - Blackhead aka, open comedo; color due to the oxidation of tyrosine to melanin upon exposure to air - Whitehead aka, closed comedo; due to inflammation or trauma to the follicle

3. Bacterial Growth The occluded follicle is rich in lipids as this is a major component of sebum This environment encourages the growth of Propionibacterium acnes (P. acnes), a bacteria that is part of the normal flora of the skin

4. Inflammation P. acnes provokes an inflammatory response by breaking down triglycerides found in sebum to free fatty acids and glycerol, and these compounds are proinflammatory P. acnes leads to further inflammation by releasing chemotactic factors that result in white blood cells (WBC) activity.

Clinical Presentation Acne may present on the face, neck, chest, back, shoulders, or upper arms Acne can be described in terms of: Type of lesion Classification of severity Lesions can take months to heal completely and fibrosis associated with healing may lead to permanent scarring

Stages of Development

Non-Inflammatory Type of Lesion Comedonal acne: Whitehead and Blackhead less than 10 in the face Inflammatory Papular: small bumps less than 5mm in diameter 10-25 in the face Pustular small bump with a visible central core of purulent material more than 25 in the face Pustulcystic acne or Nodulocystic: Nodule bump greater than 5mm in diameter

Comedonal Lesions and papular acne

Pustular acne or Inflammatory Lesions

Pustulocystic acne or Nodulocystic Lesions

Scarring

Therapeutic Objectives To prevent the formation of new acne lesions To heal existing lesions To prevent or minimize scarring

Treatment Options Non-pharmacologic Surface skin cleansing Pharmacologic Topical products Oral products

Non-Pharmacologic Treatment Surface skin cleansing with soap and water has a relatively small effect on acne because it has minimal impact within follicle Skin scrubbing or excessive face washing does not necessarily open or cleanse pores and may lead to skin irritation Use of gentle, nondrying cleansing agents is important to avoid skin irritation and dryness during some acne therapies

Pharmacologic Treatment: Topical Products Benzoyl peroxide Retinoid analogues Topical antibiotics Azelaic acid Oral products Oral Antibiotics Isotretinoin Antiandrogens and Hormones

Topical Products Treatment Vehicle cream sensitive or dry skin lotion any skin type gel oily skin solution oily skin

Benzoyl Peroxide e.g. Panoxyl 5 or 10 acne gel and cream or Akneroxid 5 gel Role in Acne Treatment: Non-antibiotic bacteriostatic agent against Propionibacterium acnes Increases the removal rate of epithelial cells and loosens the follicular plug structure Proven effective in the treatment of acne Availability Available in a wide variety of dosage forms (e.g., soaps, lotions, creams, washes, and gels) and dosages (e.g., 2.5% to 10%)

Benzoyl Peroxide cont Dosing To limit irritation and increase tolerability, begin with lowest concentration and increase either the strength or application frequency Patients should apply the product to cool, clean, dry skin no more than twice daily Common Side Effects Dryness and irritation May bleach or discolor some fabrics

Retinoid Analogues Role in Acne Treatment Increases cell turnover in the follicular wall Decreases cohesiveness of cells, leading to extrusion of the comedones and inhibition of new comedo formation Effectiveness in the treatment of acne is well documented

Retinoid Analogues cont Examples Tretinoin (topical vitamin A acid e.g. Retin A gel or cream) Availability wide variety of dosage forms and concentrations Dosing applied once nightly Side Effects skin irritation, erythema, peeling, increased sensitivity to sun exposure, wind, or cold Adapalene (Differin) Availability 0.1% gel, cream and alcoholic solution Dosing - applied once daily at night or in the morning Side Effects minimal irritation Tazarotene (Acnee free gel, cream and lotion) Availability 0.05% and 0.1% gel or cream Dosing applied once nightly Side Effects irritation, erythema, burning, stinging

Topical Antibiotics Role in Acne Treatment - Both erythromycin and clindamycin have demonstrated efficacy and are well tolerated Availability - Wide variety of dosage forms and concentrations - Also available in combination with benzoyl peroxide Dosing - Erythromycin applied once or twice daily - Clindamycin (e.g. Dalacin T lotion) applied once or twice daily - In combination with benzoyl peroxide applied once or twice daily Common Side Effects - Development of resistance by P. acnes

Azaleic Acid Role in Acne Treatment Reported to possess comedolytic, antiinflammatory and antibacterial properties Availability 20% cream e.g. Skinoren or Azaderm cream Dosing Applied twice daily on clean, dry skin Side Effects Mild transient burning, pruritus, stinging and tingling

Other topical Products Salicylic Acid 0.5-2% Irritant keratolytic agent applied twice daily skin dryness and irritation Sulfur 3-8% Keratolytic agent and antibacterial offensive color and odor Resorcinol Keratolytic agent more effective when combined with sulfur Example of the above three in combination Sacnel soap

Oral therapy (Indications) Moderate inflammatory acne non responsive to topical therapy Pustulocystic acne

Oral Antibiotic Role in Acne Treatment Standard of care in the management of moderate and severe acne as well as in treatment-resistant forms of inflammatory acne Examples Tetracycline least expensive and most often prescribed for initial therapy Doxycycline (vibramycin) more effective than tetracycline Minocycline (minocin) reserved for patients who do not respond to other oral antibiotics or topical products; superior to doxycycline in reducing P. acnes Erythromycin effective, but use is limited to those who cannot use the tetracyclines (e.g. pregnant women or children under 8 y.o.) Trimethoprim-Sulfamethoxazole (Septazol and sutrim) effective, but use is limited to those who cannot use the tetracyclines or erythromycin, or in case of resistance to these antibiotics Clindamycin (Dalacin C Cap.) use is limited because it causes diarrhea

Oral Antibiotics cont Dosing - Tetracycline 250-500mg twice to four times daily - Doxycycline 50-100mg once to twice daily - Minocycline 50-100mg once to twice daily - Erythromycin 250-500mg twice daily - Trimethoprim-Sulfamethoxazole 160/800mg twice daily - Clindamycin use is limited by diarrhea - Combined with topical therapy Common Side Effects - Candidiasis mainly vaginal, photosensitivity, diarrhea

Isotretinoin (e.g. Roaccutan10 or 20 mg Cap.) Role in Acne Treatment - Indicated for severe nodular or inflammatory acne in patients unresponsive to conventional therapies, for scarring, for those with chronic relapsing acne and for acne associated with severe psychological distress - Decreases sebum production, changes in sebum composition, inhibits P.acnes growth within follicles, inhibits inflammation ipledge program - Isotretinoin is a potent teratogen, and thus should only be prescribed by physicians knowledgeable in its appropriate administration and monitoring - ipledge is a mandatory distribution program in the United States for isotretinoin - Female patients of child-bearing potential must only be treated with this agent if they are participating in ipledge - Physician enters the patient s information into the ipledge website - Dispensing pharmacist interviews patient and verifies patient information on website - Patient has to sign a consent form to comply with the program

Isotretinoin cont Dosing - 0.5-2.0 mg/kg/day - Drug is usually given for a 20 week course of therapy - Lower doses can be used for a longer time period, with a total cumulative dose of 120-150 mg/kg Common side effects - Teratogenicity, Dry mouth, nose and eyes - Increases in cholesterol, triglycerides and glucose - Mood disorders, depression and suicidal ideation.

Antiandrogens and Hormones Role of hormones (e.g. Diane 35 tab.) in Acne Treatment - Acne associated with hirsutism, menstrual irregularity and alopecia as well as women desiring contraception - Estrogen-containing oral contraceptives can be useful in the treatment of acne in some women - Currently FDA-approved products for the treatment of acne include Ortho Tri-Cyclen (norgestimate with ethinyl estradiol) and Estrostep (norethindrone acetate with ethinyl estradiol) as both show to be equally efficacious - The effect of other estrogen-containing contraceptives (e.g., transdermal patches, vaginal rings) has not been studied

Antiandrogens and Hormons cont Spironolactone (Aldactone) can be used as an androgen antagonist Oral corticosteroids (e.g. Prednisone in 20 mg/day or its equivalent) can be used to treat severe acne. Oral corticosteroids provide quick improvement for important events like wedding. Topical corticosteroids are not effective

Acne Treatment and Therapeutic Strategies Comedonal lesions Topical retinoid Azelaic acid Salicylic acid If results unsatisfactory Increase strength or change medications Mixed comedonal lesions and papulopustules Retinoid+topical antibiotics Retinoid+benzoyl peroxide Retinoid+benzoyl peroxide+topical antibiotics Azelaic acid+benzoyl peroxide Azelaic acid+topical antibiotics If results unsatisfactory prescribe topical retinoid+ course of oral antibiotics Papules and pustules Benzoyl peroxide If results unsatisfactory switch to or add topical antibiotics If results unsatisfactory add course of oral antibiotics Cystic lesions Prescribe course of oral antibiotics + mixed comedonalpapulopustular topical therapy If results unsatisfactory consider referral to dermatologist for oral isotretinoin therapy