Articles

Acne

Introduction

Acne vulgaris, the most common skin disease, affects 80% of the population between the ages of 12 and 25. (1) It is generally self-limiting, however, may persist for years and in severe cases, may potentially lead to scarring and disfigurement. The lesions of acne are generally classified as inflammatory or noninflammatory, and include comedones, papules, pustules, and nodules, or cysts, and occur most frequently on the face, neck, chest, and back.

The pathogenesis of acne is proving to be increasingly complex. It involves the interaction of enzymatic, immunologic, and chemotactic effects on normal cutaneous microflora; hormonal influences; abnormal keratinization of the sebaceous follicular duct wall; increased sebum production; follicular fragility; and host responsiveness. (2)

One of the pathogenic factors in acne is sebum, produced by sebaceous glands. Sebaceous glands are located throughout the body except for the palms of the hands, soles and dorsa of the feet, and the lower lip. Each person has approximately 5,000 sebaceous follicles. These glands are the largest and most numerous on the face, back, chest, and upper outer arms. Sebaceous glands are large at birth, and then reduce in size until adolescence. They once again enlarge during pre-puberty with changes in hormone levels influencing sebaceous gland secretion. The expression of the disease during puberty is due to increased production and release of sebum by the sebaceous glands. Comedones, or small cysts, appear as a result of the blockage of hair follicles by excess sebum and keratinous material. The activity of lipophilic yeast (P. orbiculare) and bacteria (Proprionobacterium acnes) within the comedones releases free fatty acids from sebum, causes inflammation within the cyst, and results in rupture of the cyst wall. (3)

The hormonal mechanism by which sebum levels are increased occurs as testosterone is converted to dihydrotestosterone in the skin, which acts directly on the sebaceous gland to increase its size and metabolic rate. Estrogens, however, have a less well-defined mechanism, and decrease sebaceous gland secretion. Sebaceous cells mature, die, fragment, and extrude into the sebaceous duct, where they combine with desquamating cells of the lower hair follicle, and finally arrive at the surface of the skin as sebum. Early acne lesions result from blockage of the follicular canal. Increased amounts of keratin, also induced by hormonal changes, mix with sebum, which has been modified by the action of resident flora (P.acnes). This increases the number of cornified cells which remain adherent to the follicular canal. This is known as retention keratosis and occurs just above the opening of the sebaceous gland duct to form a plug.

The importance of altered keratinization of cells within the follicle is not completely understood. It has been observed, though, that increased production of loosely adherent keratin cells has been correlated with obstruction of the follicles seen in comedo formation. It is unknown whether this activity is inherent or secondary to irritation and other factors. (4)

Proprionobacterium acnes, the resident flora of which we have spoken is an anaerobic diphtheroid. As it interacts with the increased amount of sebum, it produces lipases, proteases, hyaluronidase, and chemotactic factors. The interaction creates free fatty acids, which are primary irritants and are very comedogenic. Also, chemotactic factors attract neutrophils. Neutrophils release hydrolases that weaken the follicular wall. As a result, the wall thins, becomes inflamed (red papule), and ruptures, releasing part of the comedo into the dermis. If this occurs, an intense foreign body inflammatory reaction occurs, resulting in the formation of a pustule or cyst.

The earliest lesions most often seen in adolescence are mildly inflamed or non-inflamed comedones on the forehead. Comedones may be open (blackhead), or closed (whitehead). The contents of closed comedones are usually not easily expressed, and are often the precursors of the inflammatory lesions of acne vulgaris. It is unsure where open comedones get their black color. It is not from accumulation of dirt, and may not even be the accumulation of melanin, which was the source most recently thought to be the cause. Open comedones generally do not result in inflammatory acne lesions, are easily expressible, and contain oxidized, darkened, oily debris.

The severest forms of acne are most frequently seen in males, but acne is generally more persistent in females. Also, females tend to have flare-ups prior to menstrual periods. This may continue until menopause. Low grade, persistent acne is often found in professional women. One author postulates that chronic stress leads to enhance secretion of adrenal androgens, resulting in sebaceous hyperplasia and subsequent production of comedones. (5)

Acne grading is accomplished by evaluating types and numbers of lesions, complications, including drainage, hemorrhage or pain, and total impact of the disease on the person and their self-esteem. Psychosocial impact becomes very important in cultures that place much emphasis upon physical appearance. These factors, along with previous failures of response to treatment are taken into account, when determining the severity.

Inflammatory lesions include papules, pustules, and nodules (cysts). Papules are less than 5mm in diameter. Pustules have a visible core of purulent material. Nodules are greater than 5mm in diameter and may become suppurative or hemorrhagic. (6) Graded as mild, moderate, or severe, lesions are also evaluated for ongoing scaring, persistent purulent, and/or serosanguineous drainage, and presence of sinus tracks.

Acne is considered an inherited disease, although it is impossible to know which members of a family may suffer from the disease, and which members will not. Acne is not caused by greasy foods, and is not caused by dirt. Avoiding all greasy foods may help curb obesity, but will likely not affect a patient’s acne. Excessive washing of the skin to remove dirt may actually interfere with some treatment programs.

External causes of acne include occupational acne, which involves acne as a result of exposure to certain industrial solvents or other chemicals, particularly chlorinated hydrocarbons and coal tar derivatives, and acne mechanica, which is caused by mechanical irritation of the skin by chin straps or forehead guards often seen inside sports helmets.

Categories of severe acne known as nodulocystic acne include localized cystic acne, in which a few cysts appear on the face, chest or back, and diffuse cystic acne, which involves a wider area of cystic lesions. Pyoderma faciale is the term used for inflamed cysts localized on the face in females. Acne conglobata describes a highly inflammatory form of nodulocystic acne. Acne fulminans is a rare ulcerative form of acne with unknown etiology. Necrotic acne is accompanied by systemic symptoms of arthralgia or severe muscle pain, or both. 40% of patients with Acne fulminans experience painful bone lesions.

Statistic

National Institute of Arthritis and Musculoskeletal and Skin Diseases. 2001.

  • Nearly 17 million Americans have acne
  • Acne is the most common skin disease in the US
  • Between the ages of 12 and 24, almost 85% develop acne

Signs and Symptoms

[span class=alert]The following list does not insure the presence of this health condition. Please see the text and your healthcare professional for more information.[/span]

Acne may be considered inflammatory or noninflammatory. Early acne usually presents as noninflammatory or mildly inflammatory closed comedos (whiteheads) or open comedos (blackheads). Once an inflammatory response has occurred, the acne may appear as erythematous papules, superficial pustules, or in cases of more severe acne, deep pustules or suppurative nodules. These may be accompanied by pain and sometimes hemorrhage.

Noninflammatory (obstructive)

    Closed comedones (whiteheads) Open comedones (blackheads)

Inflammatory

    Papules Pustules Erythema Pain Hemorrhage Nodules or cysts

Treatment Options

Conventional

Acne is a multifactorial process and may require multiple treatment approaches for control. Though various etiologic theories exist, acne is primarily due to an alteration in the pattern of keratinization within the follicle. (7) In most patients, therapy should be directed at correcting abnormal keratinization and inhibition of P. acnes to control inflammatory acne. (8) Systemic therapy is generally reserved for patients who are at risk for scarring, or who do not respond to topical therapy. Aggressive therapy may be necessary for the patient with inflammatory acne.

Removal of acnegenic substances should be the first principle of therapy. Some cosmetics, oils, and creams may be capable of producing comedones, and their use should be stopped. Androgens are acnegenic. Changing from an oral contraceptive containing androgenic progestins (eg norethindrone, norgestrel) to one with more estrogenic ones can help. (9) Steroids, iodides, and bromides may also increase the occurrence of acne.

Retinoic acid (Tretinoin, Retin-A) is a frequently used, and is currently the only comedolytic agent available. It is available in cream, gel, and liquid vehicle. Dryness and irritation are the greatest potential side effects, and occur with greater frequency with the gels and hydroalcoholic solutions. Most patients tolerate cream vehicles, which have less irritating effects. Strengths of cream available include 0.025%, 0.05%, and 0.1% concentrations. Most patients should start using the 0.025% cream once daily. The gel is available in 0.01% and 0.025%, and the liquid at 0.05% concentration. The liquid is most frequently used on patients with severe involvement on the back and chest who tolerate the cream and gel but are not getting the desired response.

The action of topical retinoic acid is to thin the outer horny layer of the epidermis. This reduces hyperkeratosis and loosens existing comedones. It also helps prevent the formation of new lesions. Also available, as an alternative to retinoic acid, is adapalene, a retinoid-mimetic topical gel. Some studies have shown results even slightly better than retinoic acid, when comparing numbers of lesions at week 12. The advantage of adapalene is that it is better tolerated, resulting in less erythema, pruritis, burning, stinging, and peeling. Tazarotene, a prodrug and new generation retinoid is also available. The compound seems to have no advantage over retinoic acid and side effects are similar to tretinoin gel.

Benzoyl peroxide is a topical agent frequently used in combination with retinoic acid. It is available over-the-counter in the form of soaps, lotions, creams, and gels. The strength ranges from 2.5-10 percent and is applied every other day initially, then twice daily thereafter. If used in combination with retinoic acid, it is generally used once daily approximately 8 to 12 hours after the retinoic acid. Benzoyl peroxide is decomposed on the skin by cysteine, liberating free oxygen radicals that oxidize bacterial proteins. (10) Daily application of 10% benzoyl peroxide for 2 weeks can reduce free fatty acid levels by 50% and P.acnes levels by 98%. Benzoyl peroxide increases the sloughing rate of epithelial cells, loosens the follicular plug structure, and thus possesses some degree of comedolytic activity. (11)

The combination of retinoic acid and benzoyl peroxide has largely replaced the use of products containing sulfur, salicylic acid, and resorcinol. These agents are considered keratolytic and mildly antibacterial. They may be used alone, or sometimes in combination in efforts to achieve a synergistic effect. The unpleasant side effect of the odor of sulfur products often limits their use, and a brown scale is sometimes caused by the use of resorcinol.

Topical antibiotics may also be used to treat mildly inflammatory acne. This is a preventive form of therapy that does little to help pre-existing lesions. The antibiotics used are clindamycin, erythromycin, and tetracycline and all are bacteriostatic for P.acnes. Clindamycin is available as a 1% solution, gel, or lotion applied twice daily. Erythromycin comes as a solution, gel, or powder in 1.5-2% strengths to also be applied twice daily. Tetracycline topical is available as a 2.2% solution to be applied twice daily. Each product has potential side effects that should be considered and may limit their use.

Systemic antibiotics are frequently used to treat inflammatory acne and are the best means of preventing new inflammatory lesions. Since they have no effect upon existing lesions, it may take 6-8 weeks of therapy before clinical results are noticed. The antibiotics most frequently used are tetracycline, erythromycin, and clindamycin. Ampicllin, trimethoprim/sulfamethoxizole, and cephalosporins may also be used. The most cost effective treatments are generic erythromycin or tetracycline. The dosage is often started at 250mg four times daily, then the dose may be gradually decreased to the lowest effective maintenance dose. This dosage regimen is often difficult to maintain, so while more expensive, many physicians opt for minocycline or doxycycline since their absorption is not affected by food, and they are given on a twice-daily regimen.

Intralesional corticosteroids may be used on patients with nodulocystic lesions. Triamcinolone acetonide 2-2.5mg/ml in saline is directly injected into specific lesions. This treatment has been shown to hasten involution of lesions and reduce scarring. Some dermatologists may also use cryotherapy, freezing tissues with liquid nitrogen. Caution must be exercised to avoid excessive freezing and tissue destruction.

Isotretinoin therapy is reserved for patients with severe recalcitrant acne that has not responded to other therapies. Its action is multifaceted in that it decreases sebum production as well as alters the composition of sebum, it inhibits the growth of P.acnes within the follicles, inhibits inflammation, and alters patterns of keratinization. Isotretinoin is a known teratogen, so appropriate precautions are essential when being administered to women of childbearing potential. It is available as a 10, 20, and 40mg capsule and doses are generally in the range of 0.5-1mg/kg/day in two divided doses. Adverse effects are numerous and are often dose-related. Approximately 90% of patients receiving isotretinoin have mucotaneous side effects. Drying of the mucosa of the eye, nose and mouth is the most common problem. Chelitis and skin desquamation occurs in 80% of patients. Other side effects have been reported, and close monitoring is vital. If tolerated, therapy is usually quite successful. Often, one or two 15 to 20 week courses bring severe acne under complete control, with little or no further therapy.

Oral contraceptives may be used in women with moderate acne, since androgen levels correlate with sebum production. The action exhibited is a decrease in unbound, biologically active androgens such as free testosterone. In 1997, the FDA approved Ortho Tri-Cyclen for use as anti-acne therapy.

Other anti-androgens occasionally used to treat acne include spironolactone, flutamide, and cyproterone acetate. Cyproterone acetate is unavailable in the United States. Use of these agents is best limited to patients with underlying increase in androgen production.

Finally, in patients with acne scars, dermabrasion, collagen injection, and other corrective procedures may be considered. (12)

Nutritional Supplementation

Niacinamide 4% Topical Gel
In an 8-week double-blind trial, 38 patients with moderate inflammatory acne vulgaris were treated with 4% niacinamide topical gel while an equal number were treated with 1% clindamycin topical gel. Patients treated with 4% niacinamide gel made slightly greater improvements compared to the patients treated with 1% clindamycin gel. (13) Because it is safe, effective, and without the antibiotic-associated risk developing resistant strains of bacteria, 4% niacinamide topical gel should be considered as an important alternative treatment for acne vulgaris.


Vitamin E

One study reported that in the presence of vitamin E deficiency orally ingested vitamin A is not absorbed. Consequently, they noted that some cases of acne vulgaris that did not respond to vitamin A therapy responded well to a combination of vitamin A and vitamin E. (14) Another study involving 98 people with acne vulgaris found that vitamin E may inhibit bacteria-induced lipid peroxidation in the sebum, resulting in a reduction of the inflammation that is often present in acne lesions. (15)


Selenium

In an open trial, men and women with moderate to severe acne were treated with a combination of 200 mcg selenium and 10 mg of vitamin E twice daily for a period of 6 to 12 weeks. Good improvements were achieved, especially in patients with pustular acne who had initially been found to have low levels of glutathione peroxidase activity. (16)


Zinc

The mechanism of zinc’s action in acne is not fully understood. However, it has been reported that both men and women with acne have lower serum zinc levels compared to healthy controls and individuals with severe acne have lower serum zinc levels than individuals with milder cases of acne. (17) , (18) In a double-blind trial, patients with inflammatory acne who were treated with 200 mg/day of zinc gluconate, corresponding to 30 mg of elemental zinc, experienced a significantly greater reduction in inflammation compared to placebo controls. (19) In other double-blind studies evaluating acne vulgaris, patients treated with 400 to 600 mg of zinc sulfate daily experience greater clinical improvement compared to placebo controls. (20) , (21) , (22)

Herbal Supplementation


Tea Tree Oil

A study compared the use of topical tea tree oil (5% gel) with benzoyl peroxide (5% gel) in the treatment of mild to moderate acne. The results of this study reported that both 5% tea-tree oil and 5% benzoyl peroxide had a significant effect in ameliorating the patients' acne by reducing the number of inflamed and non-inflamed lesions (open and closed comedones), although the onset of action in the case of tea-tree oil was slower. Encouragingly, patients treated with tea-tree oil experienced fewer side effects. (23)


Guggul

An interesting study comparing tetracycline and guggul showed surprising promise in using guggul to treat nodulocyctic acne. In this study, twenty patients were randomly assigned to a group taking either Tetracycline at 500mg twice each day for 90 days, or a group taking gugulipid twice each day for 90 days. There was a slightly better outcome with the guggul group as well as slightly fewer relapses reported. In addition, participants with oily skin seemed to respond better to the gugulipid treatment. (24)

Clinical Notes

Vitamin A: In general, acne does not respond well to oral ingestion of vitamin A ranging from 50,000 IU to 100,000 IU per day. However, one group of investigators reported highly effective results treating 123 patients with acne vulgaris at doses of 300,000 IU/day for women and 400,000 to 500,000 IU/day for men with only a couple of very minor side effects. According to these authors, high-dose vitamin A therapy can provide significant therapeutic benefits in what they describe as “stubborn, severely inflammatory acne vulgaris." (25) , (26) These authors expressed the feeling that usual cautions about vitamin A toxicity at these ranges are exaggerated. Significant improvement was accomplished within 3 to 4 months, at which time the dosage is gradually reduced and when other agents may be used to keep the condition under control.

Caution: women of child bearing age should not become pregnant while on high dose vitamin A therapy.

References

  1. Leyden JJ. Therapy for acne vulgaris. N Engl J Med. 1997;336:1156-1162.
  2. Reisner RM. Management of acne. In: Goroll AH, May LA, Mulley AG, eds. Prinary Care Medicine, Office Evaluation and Management of the Adult Patient 3rd Ed. Philadelphia: Lippincott-Raven; 1995:911-914.
  3. Swerlick RA, et al. Eczema, psoriasis, cutaneous infections, acne, and other common skin disorders. In: Fauci AS, et al, eds. Harrison’s Principles of Internal Medicine, 14th ed. New York: McGraw-Hill; 1998:303.
  4. Han NH, et al. Acne and Psorasis. In: DiPiro JT, et al, eds. Pharmacotherapy, A Pathophysiologic Approach, 4th ed. Stamford CT: Appleton & Lange; 1999:1490-1496.
  5. View Abstract: Kligman AM. Postadolescent acne in women. Cutis. 1991;48:75-77.
  6. Habif TP. Acne, In: Clinical Dermatology, a Color Guide to Diagnosis and Therapy, 3rd ed. St Louis: Mosby; 1996:148-179.
  7. View Abstract: Landow K. Dispelling myths about acne. Postgrad Med. 1997;102:94-112.
  8. Han NH, et al. Acne and Psorasis. In: DiPiro JT, et al, eds. Pharmacotherapy, A Pathophysiologic Approach, 4th ed. Stamford CT: Appleton & Lange; 1999:1490-1496.
  9. Reisner RM. Management of acne. In: Goroll AH, May LA, Mulley AG, eds. Prinary Care Medicine, Office Evaluation and Management of the Adult Patient 3rd Ed. Philadelphia: Lippincott-Raven; 1995:911-914.
  10. Arndt KA, ed. Acne. In: Manual of Dermatologic Therapeutics, 5th ed. Boston: Little & Brown; 1995:3-15.
  11. Melski JW, et al. Topical therapy for acne. N Engl J Med. 1980;302:503-506.
  12. View Abstract: Fulton JE Jr, et al. Resurfacing the acne-scarred face. Dermatol Surg. May1999;25(5):353-9.
  13. View Abstract: Shalita AR, et al. Topical Nicotinamide Compared with Clindamycin Gel in the Treatment of Inflammatory Acne Vulgaris. Int J Dermatol. Jun1995:34(6);434-37.
  14. Ayres S Jr, et al. Synergism of vitamins A and E with dermatologic applications. Cutis. May1979;23(5):600-3, 689-90.
  15. View Abstract: Ayres S Jr, et al. Acne vulgaris: therapy directed at pathophysiologic defects. Cutis. Jul1981;28(1):41-2.
  16. View Abstract: Michaelsson G, et al. Erythrocyte glutathione peroxidase activity in acne vulgaris and the effect of selenium and vitamin E treatment. Acta Derm Venereol. 1984;64(1):9-14.
  17. View Abstract: Amer M, et al. Serum zinc in acne vulgaris. Int J Dermatol. Oct1982;21(8):481-4.
  18. View Abstract: Michaelsson G, et al. Patients with dermatitis herpetiformis, acne, psoriasis and Darier's disease have low epidermal zinc concentrations. Acta Derm Venereol. 1990;70(4):304-8.
  19. View Abstract: Dreno B, et al. Low doses of zinc gluconate for inflammatory acne. Acta Derm Venereol. 1989;69(6):541-3.
  20. View Abstract: Verma KC. Oral zinc sulphate therapy in acne vulgaris: a double-blind trial. Acta Derm Venereol. Jan1980;60(4):337-40.
  21. View Abstract: Lidén S. Clinical evaluation in acne. Acta Derm Venereol Suppl (Stockh). Jan1980;89:47-52.
  22. View Abstract: Meynadier J. Efficacy and safety study of two zinc gluconate regimens in the treatment of inflammatory acne. Eur J Dermatol. Jun2000;10(4):269-73.
  23. View Abstract: Bassett IB, et al. A comparative study of tea-tree oil versus benzoylperoxide in the treatment of acne. Med J Aust. Oct1990;153(8):455-8.
  24. View Abstract: Thappa DM, et al. Nodulocystic acne: oral gugulipid versus tetracycline. J Dermatol. Oct1994;21(10):729-31.
  25. View Abstract: Kligman AM, et al. Oral vitamin A in acne vulgaris. Preliminary report. Int J Dermatol. May1981;20(4):278-85.
  26. View Abstract: Nagpal S, et al. Vitamin A and regulation of gene expression. Curr Opin Clin Nutr Metab Care. Jul1998;1(4):341-6.