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ACNEBRIEFS

THE PATHOGENESIS OF ACNE

1999

TM

Despite the advances that medical science has made in determining what factors are involved in the pathogenesis of acne, myths surrounding the causes of acne persist within the general public. It is essential that patients learn the true causes of acne so they can become active partners in their disease treatment. In this issue of Acne Briefs, James J. Leyden, MD, professor of dermatology at the University of Pennsylvania School of Medicine, Philadelphia, discusses how acne develops and which therapies inhibit the mechanisms involved in the disease.

Q. How has the understanding of the pathogenesis of acne changed the way it is treated? Dr Leyden. We now know where to aim our therapy and research. The therapies we currently have available are designed to target specific areas of acne pathogenesis. Q. What factors in the pathogenesis of acne have to be addressed to understand and treat this condition? Dr Leyden. There are 4 basic factors involved in the development of acne vulgaris. Acne arises due to blockage of specialized follicles -- the sebaceous follicles -- which are found in the face, neck, chest, and/or back. In acne patients, the sebaceous glands attached to these follicles secrete excessive amounts of sebum. It has been shown that the sebaceous glands in acne patients tend to be hyperresponsive to androgens, which are first released in the prepubertal period. Thus, these patients produce more sebum than is normal; this excessive secretion is a necessary prerequisite for the onset of acne. Second, the epithelial cells in the sebaceous follicles undergo abnormal desquamation for reasons that are not yet clear. Normally, keratinous squamae are loosely organized, but they become denser and more coherent as a result of abnormal desquamation. The combination of abnormally desquamated cells and excessive sebum forms a "plug," or microcomedo -- the precursor lesion of both noninflammatory comedones and inflammatory lesions. Third, the anaerobic bacterium Propionibacterium acnes proliferates in the lipid-rich environment of the microcomedo. The mixture of sebum and desquamated cells in a plugged follicle provides an ideal anaerobic environment for P acnes. Fourth, P acnes produces proinflammatory mediators and chemotactic factors that can cause microcomedones to inflame and evolve into papules, pustules, and nodules. Q. What are some of the proinflammatory products of P acnes?

James J. Leyden, MD Dr Leyden. P acnes can produce enzymes such as lipases, proteases, and hyaluronidases, and these enzymes also have products that can cause inflammatory changes. In addition, P acnes produces chemotoxins for neutrophils and lymphocytes, and its cell wall peptidoglycan can stimulate macrophages to produce interleukin (IL)-1, tumor necrosis factor (TNF)-, and IL-8. Q. Do all patients with acne have colonies of P acnes in their sebaceous follicles? Dr Leyden. At the onset of acne that occurs with adrenarche,

The geometric mean count of P acnes per follicle on the skin of acne patients is around 115,000, whereas on normal skin it is practically zero.

acne typically presents as noninflammatory comedones in the midforehead, nose, and chin. At this early stage, P acnes colonization has not yet occurred. With puberty, increased sebum develops, P acnes colonization occurs, and inflammatory lesions arise. Q. What about patients who have inflammatory lesions? Dr Leyden. These patients have significant amounts of P acnes. It is the presence of the bacterium and its by-products that stimulates inflammation. Q. Is P acnes endemic only to the skin of acne patients? Dr Leyden. P acnes is present in very low numbers even on normal skin. The geometric mean count of P acnes per follicle on the skin of acne patients is around 115,000, whereas on normal skin it is practically zero. Q. Are there any other types of bacteria or organisms on the skin that contribute to acne? Dr Leyden. Although staphylococci, micrococci, and Pityrosporum yeasts can be found within the follicle, none has been associated with the development of acne. Furthermore, the surface staphylococci and micrococci and follicular Pityrosporum all are typically resistant to antibiotics such as tetracycline and erythromycin, and yet these drugs obviously are helpful in acne. Q. Is it only the amount of sebum that is important in comedogenesis, or does the composition have an effect, too? Dr Leyden. It has been demonstrated that acne patients have less linoleic acid in their sebum than do age-matched controls. Some have suggested that this deficiency may cause the abnormal desquamation of follicular epithelial cells that leads to the formation of microcomedones and comedones. This theory is supported by research showing that systemic linoleic acid deficiency increases desquamation of the surface epithelium. A more localized version of this effect may be taking place within the follicle. Q. What are some of the other components of sebum? Dr Leyden. Sebum reaching the surface is composed primarily of glycerides and free fatty acids. It also contains wax esters, squalene, cholesterol esters, and cholesterol. Free fatty acids and squalene are probably the most comedogenic elements. Q. What component of sebum serves as a nutrient for P acnes? Dr Leyden. The triglycerides. Q. Does eating a high-fat or high-cholesterol diet trigger excess sebum production? Dr Leyden. It is a myth that eating fatty foods, fried foods, or chocolate can cause acne. Diet has not been shown to influence sebum production. Changing the diet will not ameliorate acne. The only things that can suppress sebum production are starvation, radiographic therapy, isotretinoin, and some of the antiandrogens and estrogens in oral contraceptives. Q. Why does the myth persist that acne is caused by poor hygiene? Dr Leyden. Sometimes when patients see pigmented acne lesions such as blackheads, they erroneously believe their skin is "dirty." The dark color of blackheads is not caused by dirt, however. It's the result of interference in the transmission of light through the compacted follicular epithelial cells. Patients have to be educated that acne is not caused by poor diet or poor hygiene, but by an interaction of the 4 factors listed earlier. Q. Can acne develop in any part of the follicle, or is it limited to a specific region? Dr Leyden. Comedogenesis takes place in the infrainfundibular region of the follicle, which is the area between the sebaceous gland and the acrainfundibulum. Q. What happens to the follicle during comedogenesis? Dr Leyden. As keratinous material gathers in the sebum-filled follicle, the follicular wall thins and swells. Often, the follicle expands so much that the sebaceous glands atrophy.

HOW WOULD YOU TREAT THIS PATIENT?

Case 1 A 13-year-old girl is brought in by her parents. Her mother is worried because she had "bad acne" as a teenager, and wants to spare her daughter the same fate. The mother has no evidence of acne scarring. The father says he never really had acne -- "just a few zits". The girl's skin is relatively clear, though she has a few whiteheads.

At this point, since there are no lesions, I would follow the patient closely. With the onset of lesions, I would use topical retinoids. As sebum production increases, I would add antibiotics topically and be prepared to increase therapy since things often change abruptly in patients with bad acne in their background.

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[A]cne patients have less linoleic acid in their sebum than do age-matched controls.... [T]his deficiency may cause the abnormal desquamation of follicular epithelial cells that leads to the formation of microcomedones and comedones.

In blackheads, or open comedones, the opening of the follicle (ie, the pore) is patulous. Whiteheads, or closed comedones, have narrow follicular openings. The keratinous material in blackheads is usually arranged in a lamellar, concentric pattern, which interferes with the transmission of light so that the plug appears dark. In whiteheads, the arrangement is looser. Whiteheads appear as small, pale, raised lesions without any discernible center. Q. How do inflammatory lesions develop? Dr Leyden. The chemotactic and inflammatory products of P acnes cause inflammation in the follicular wall, which can then rupture. The keratinous material that is released into the dermis causes further inflammation, which manifests as a papule or nodule. Q. Do patients usually have either just inflammatory or noninflammatory lesions? Dr Leyden. Acne is a pleomorphic disease and most patients have a variety of lesions. The microcomedo, as I mentioned earlier, is a precursor to all other acne lesions. This microscopic precursor lesion can evolve into either blackheads or whiteheads. Inflammatory lesions develop from the precursor microcomedones if P acnes proliferation occurs and proinflammatory mediators are produced. Blackheads do not proceed to inflammatory lesions unless they have been traumatized by the patient. Q. Why do some patients have only mild disease, while others develop severe acne? Do they have more P acnes, or more androgen stimulation, or a more susceptible type of follicle? Dr Leyden. Severity of acne most likely reflects differences in host responses to inflammatory stimuli. Q. When does acne first develop? Dr Leyden. That varies by individual. Even neonates may have a form of acne, which is more commonly a noninflammatory process, although inflammatory lesions can occur. Generally, acne begins in the prepubertal period -- anywhere from age 8 to 13 -- but it is not uncommon in girls of 7 years. The adrenal glands have matured and begin to release increased amounts of adrenal androgens. Secretion of sebum by the sebaceous gland is triggered by androgens. During this initial period, the child may develop noninflammatory comedones in the "T-zone" -- the forehead, chin, nose, and paranasal areas. These precursor lesions are solely a result of increased sebum production and abnormal desquamation within the follicle. As the child becomes pubescent and the gonads mature, androgen production increases, as does sebum secretion. The follicular environment thus is conducive to the proliferation of P acnes colonies, which can instigate the development of inflammatory lesions.

I would begin treating this patient with topical retinoids and a benzoyl peroxide/erythomycin combination. If he hasn't improved significantly after 2 or 3 months, I might add minocycline or doxycycline.

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In most patients, acne subsides by the mid-20s. Many people, however, continue to have acne well into their 40s. Some women may even develop acne for the first time in their 20s, 30s, or 40s. This type of late-onset acne may be hormonally related. Acne flares in this type of acne often correlate to the menstrual cycle. Q. Why do some patients continue to have acne throughout their adulthood? Dr Leyden. It is not yet clear why acne subsides in some but persists in others. I have several hypotheses but no data exist. Q. Acne seems to be almost universal among teenagers, and fairly common in older people, too. What is the prevalence of acne in the United States? Dr Leyden. It is estimated that almost 80% of people will have acne at some point between the ages of 11 and 30 years. It can, of course, persist beyond that point or develop at an earlier age. Q. Acne is generally regarded as an inconsequential disease. Would you agree with that viewpoint? Dr Leyden. No. Acne can have serious repercussions because it often has a negative impact on a patient's self-esteem and quality of life. Acne has been associated with emotional problems, social withdrawal, and depression. Clearing acne often reverses these effects.

HOW WOULD YOU TREAT THIS PATIENT?

Case 2 A 15-year-old boy presents with moderate inflammatory and comedonal acne. He has never been to a dermatologist before and has never tried over-the-counter medications. He is involved in sports and other extra-curricular activities at school but is worried that if his acne worsens, it will make him unattractive to girls.

We can use topical retinoids, such as adapalene (Differin®), tretinoin (Retin-A®, Retin-A MicroTM, or Avita®), or tazarotene (Tazorac®), to correct abnormal keratinization; anti-androgen agents and isotretinoin to decrease sebum production; and antimicrobials and antibiotics to kill P acnes...

Q. Do most acne patients consult a dermatologist? Dr Leyden. Unfortunately, no. Many people with acne-- especially teenagers--try to self-treat with over-the-counter medications. Q. Why is self-treating acne generally ineffective? Dr Leyden. Milder forms of acne can be effectively treated by over-the-counter drugs. Since most people don't understand what causes acne, however, the therapies they choose may have no inhibitory effects on pathogenic factors. They will often use harsh or abrasive cleansers because they think their skin is dirty, but these simply irritate the skin and exacerbate the acne. Sometimes they will pick a product that is helpful, such as a benzoyl peroxide product that can kill P acnes, but they'll use it inappropriately. Rather than applying the product to the entire face, they will try to spot treat their lesions and will not continue therapy after the initial lesions have cleared. Thus, their acne persists. Dermatologists have access to a wide array of targeted therapies that can shut down acne pathogenesis. We can use topical retinoids, such as adapalene (Differin®), tretinoin (Retin-A®, Retin-A® MicroTM, or Avita®), and tazarotene (Tazorac®), to correct abnormal keratinization; anti-androgen agents and isotretinoin to decrease sebum production; and antimicrobials and antibiotics to kill P acnes, thereby eliminating inflammatory factors. Q. You mentioned that the sebaceous glands in acne patients are sensitive to hormones. Which hormones stimulate sebum secretion within the follicle? Dr Leyden. The most important hormones are testosterone and dihydrotestosterone (DHT). Within the sebaceous glands, testosterone is converted by 5-reductase into DHT, which is up to 10 times more potent than testosterone as an androgen receptor agonist. Some drugs have been developed that can inhibit the type II isoenzyme of reductase, potentially limiting the production of DHT. These drugs, however, have not been successful in reducing the production of sebum, which has led investigators to conclude that the type I isoenzyme is the active form within the sebaceous glands. The adrenal hormone dehydroepiandrosterone sulfate (DHEAS) can be converted to testosterone; studies have associated high serum levels of DHEAS with the initiation of acne in girls. Q. Do acne patients have higher levels of androgens than do people with normal skin? Dr Leyden. Rather than having overproduction of androgens, most acne patients probably have sebaceous glands that are hypersensitive to the effects of androgens. That being said, acne is fairly common in patients with excessive levels of androgens, too. Q. Who is likely to have excess androgen, and how can these patients be recognized? Dr Leyden. Women in their 20s or older who have acne along with abnormal periods, infertility, hirsutism, or other signs of virilization may have excess androgen production. These patients need to undergo a hormonal work-up and should be referred for a gynecologic examination, too. Most women with hormonal flares of acne, however, have normal androgen levels. Again, their sebaceous glands are probably hypersensitive to androgens. Q. Is neonatal acne influenced by maternal hormones during gestation? Dr Leyden. There are a number of theories regarding neonatal acne. Some believe it to be related to maternal hormones, others to high prenatal levels of androgens. Some have proposed that it is not acne at all, but a reaction to infection with Malassezia species (eg, Malassezia furfur). Q. What inherited factors may influence the presence or severity of acne?

To avoid scarring over time, I would perform intralesional injections of steroids and start her on oral isotretinoin.

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HOW WOULD YOU TREAT THIS PATIENT?

Case 3 A 22-year-old woman is worried about her acne, which is now affecting her chest and back as well as her face. She has been spot-treating with over-the-counter benzoyl peroxide for years, but it is not helping clear these lesions.

Dr Leyden. We don't know what specific genes are involved in acne. It is clear, however, that acne has a genetic component. When a child has one or both parents who had severe acne, he or she will have a higher than average risk for severe acne.

To achieve optimal results, topical retinoids should be used for several months... Combination therapy with antibiotics, either topically or systemically, makes sense for most patients.

Q. Can potentially severe acne be prevented if identified soon enough? Dr Leyden. Possibly, although this has not been formally demonstrated. The earlier acne is treated, the more likely it is that inflammatory lesions, sinus tracts, scarring, and other complications of acne can be prevented. That is why it is important that patients be educated to continue with maintenance acne therapy even after their initial lesions have cleared. Q. Is it ever "too soon" to treat acne? Dr Leyden. No. Q. What kinds of therapies are best for rendering the environment of the follicle less suitable for P acnes proliferation? Dr Leyden. Topical retinoids such as adapalene, tretinoin, or tazarotene are the treatment of choice for normalizing follicular epithelial desquamation and making the environment less favorable for P acnes proliferation. Salicylic acid can be used as an alternative in very mild cases. Adapalene (Differin) is a naphthoic acid that has retinoid-like activity. It is available in either a 0.1% gel or a 0.1% solution. The advantage with adapalene is you can get the same clinical benefits that you do with the original tretinoin, but the irritation profile is lower than Retin-A. Because the retinoid tretinoin (Retin-A) can be irritating to some patients, they should be started on a low concentration of the cream, which is available in 0.025%, 0.05%, and 0.1% concentrations, or the gel, which comes in 0.01% and 0.025% concentrations. If the patient tolerates the medication, the dose can be raised in increments. Newer, less irritating forms of tretinoin are 0.025% cream or gel (Avita) and a form of the drug that is delivered via microspheres (Retin-A Micro). Another new retinoid molecule is tazarotene (Tazorac), which is effective in acne. Q. Do the topical retinoids ever exacerbate acne? Dr Leyden. The earliest topical retinoid, Retin-A, in a hydroalcoholic vehicle sometimes caused outbreaks of lesions at the onset of therapy. Q. You mentioned that various therapies address different aspects of acne pathogenesis. How are the topical retinoids used to reverse abnormal desquamation? Dr Leyden. Adapalene, tretinoin, and tazarotene normalize the desquamation process, which results in a "less plugged" follicle. Monotherapy with topical retinoids is usually reserved for preteenagers or those in their early teens, who typically present with increased sebum and noninflammatory lesions but are not yet colonized with P acnes. It can, however, be used in older individuals who have no or minimal inflammatory lesions. Q. If the patient's skin doesn't clear within a couple of weeks, should the dermatologist change the patient's prescription? Dr Leyden. To achieve optimal results, topical retinoids should be used for several months. Even after the patient's complexion has remained clear for some time, therapy should be continued until it is certain that no new lesions are forming. Combination therapy with antibiotics, either topically or systemically, makes sense for most patients. Q. Why is treating comedonal acne with topical retinoids so important? Dr Leyden. It is desirable, in this initial phase of acne development, to disrupt the creation of an environment favorable to P acnes. Retinoids achieve this better than any other therapy. Some patients with very mild disease may also respond to topical salicylic acid, which can be bought over the counter in 0.5% and 2% hydroalcoholic formulations. It has some comedolytic activity, though far less than the topical retinoids. Isotretinoin also interrupts abnormal desquamation of the follicular epithelium in sebaceous follicles, but this drug should be reserved for severe or intractable cases of acne. Q. What is the mechanism of action by which the topical retinoids exert their effects? Dr Leyden. That, too, is under investigation. We know that they bind with varying retinoid receptors within the follicle, and that accounts for variability in the adverse effect profiles between the different drugs. But how the retinoids manage to reverse abnormal desquamation and prevent follicular plugging is still unknown. Q. How do you treat mild cases of inflammatory acne? Dr Leyden. Mild inflammatory acne most often affects young teenagers and women in their 20s. In this patient group, it is important to tackle the third component of acne pathogenesis, which is colonization with P acnes. I would recommend daily applications of a topical retinoid along with a topical antimicrobial and topical antibiotic combination. My favorite combination is benzoyl peroxide with erythromycin (Benzamycin®). This agent not only suppresses P acnes but also minimizes emergence of resistant strains of acne. I use topical retinoids to counteract the microcomedo, which is present even if clinical expression of noninflammatory lesions is not seen. Q. Are the topical retinoids and antimicrobials used only for the beginning stages of acne, or can they be combined with other agents to control more severe forms of the disease? Dr Leyden. The majority of patients, as I mentioned before, will have a combination of noninflammatory and inflammatory lesions and therefore will require combination therapy to reduce follicular plugging and kill P acnes.

ACNEBRIEFS · PAGE 5

Two of the most popular combinations for mild to moderate inflammatory acne are (1) adapalene, tretinoin, or tazarotene with benzoyl peroxide, and (2) topical retinoids with a benzoyl peroxide/erythromycin combination.

Two of the most popular combinations for mild to moderate inflammatory acne are (1) adapalene, tretinoin, or tazarotene with benzoyl peroxide, and (2) topical retinoids with a benzoyl peroxide/erythromycin combination. Clindamycin and erythromycin applied topically are also effective, but I don't use them alone because of the emerging problem of antibiotic resistance. Q. Should patients be advised to apply topical retinoids and antibiotics directly to the lesions? Dr Leyden. Topical retinoids and antibiotics should be applied all over the general area of acne. Spot treatment does not work in acne therapy, period. The strategy is to prevent new lesion formation. Q. Can topical retinoids be used on any part of the body affected by acne? Dr Leyden. As with all acne medications, these can be used wherever lesions appear, whether on the face, neck, or trunk. Q. Do patients ever discontinue topical therapy too early? Dr Leyden. That can be a problem. Again, it is important for patients to understand that clearing the lesions is only half the battle. Acne is a chronic condition, so some sort of maintenance therapy should be instituted over the long term, then gradually withdrawn when it appears certain that the condition has resolved. Q. At what stage of acne pathogenesis are systemic antibiotics required? Dr Leyden. Usually, systemic therapy is based on the extent and severity of the disease. Some patients may need to use both an oral and a topical version of a single antibiotic, particularly once the dose of oral antibiotic is reduced -- after a period of at least 2 to 4 months. Q. What are some of the antibiotics that can be used in acne? Dr Leyden. Available choices include tetracycline, which should not be used in children whose permanent teeth have not yet developed, erythromycin, doxycycline, minocycline, and trimethoprim. Q. Do antibiotics have any comedolytic effects? Dr Leyden. They appear to have an indirect influence on comedogenesis. Clinical trials with topical or systemic antibiotics alone have shown that there may be up to a 20% reduction of noninflammatory lesions, too. In contrast, topical retinoids reduce noninflammatory lesions by approximately 60%. These results suggest that P acnes produces comedogenic factors, such as free fatty acids. More research needs to be done in this area. Q. Once the lesions clear, should the patients discontinue taking the antibiotics? Dr Leyden. Patients should not suddenly discontinue antibiotic therapy once their complexion begins to improve. To prevent the formation of new papules and pustules, P acnes must be suppressed over the long term. Combination with topical retinoids makes sense for most patients requiring systemic antibiotics. Q. How does antibiotic resistance affect acne therapy? Dr Leyden. Strains of P acnes that are less sensitive to antibiotics are becoming more prevalent. Up to 60% of patients have at least some insensitive strains. This trend is not a good one. While less sensitive or resistant strains account for a small proportion of total P acnes in most patients, it is only a matter of time before this problem becomes more serious. Q. Is there any way to identify patients who harbor antibioticresistant P acnes? Dr Leyden. In general, those who have been treated with longterm, sequential antibiotics are most likely to have resistant strains. Also, if they do not respond well to antibiotic therapy, or if they relapse after a period of doing well, they probably carry resistant strains. Q. Is antibiotic therapy adequate for patients whose inflammatory lesions are larger than usual?

I would start her on a topical retinoid in conjunction with an oral antibiotic. I'd choose the oral form because it works faster than topical antibiotics.

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HOW WOULD YOU TREAT THIS PATIENT?

Case 4 A 16-year-old girl wants to "get rid of" her acne for the prom, which is 2 months away. She has used numerous over-the-counter products, mainly cleansing pads and ointments. She has never been to a dermatologist before.

Dr Leyden. Patients with large lesions can be treated with a local injection of a corticosteroid. This will help reduce inflammation.

Q. What about patients with nodular cystic lesions? Dr Leyden. Although these patients may respond to oral antibiotic therapy alone, some may have an incomplete response. In these cases -- particularly if the patient also has evidence of scarring -- the systemic retinoid isotretinoin is required. In women, hormonal therapy -- either alone or in combination with spironolactone -- is another option. Q. What kind of adverse effects can be expected with isotretinoin? Dr Leyden. This drug is very effective and is associated with adverse effects such as arthralgia, stiffness and tendinitis, and elevated serum lipid concentrations in a small percentage of patients. It is also teratogenic; therefore, it cannot be used in women of childbearing age unless they first undergo a pregnancy test, which must be negative, and use effective contraception during the treatment period plus 1 month after treatment ends. Q. Does isotretinoin linger in the patient's system after therapy is discontinued? Dr Leyden. The drug is not stored in body tissues. Blood levels are back to pretreatment baseline within 5 to 7 days. Q. How long must patients continue taking isotretinoin to obtain the best results? Dr Leyden. The best results are seen with a cumulative dose of 120 to 150 mg/kg of body weight. I personally prefer the 150 mg/kg dose. Q. Does acne ever worsen during the initial stages of isotretinoin therapy? Dr Leyden. If the patient's acne worsens during initiation of therapy, the lesions can be controlled with corticosteroids. In some patients, temporarily reducing the dose is necessary. Almost everyone, however, will go into remission eventually. Q. How many courses of treatment must a patient undergo with this drug? Dr Leyden. Research has demonstrated that up to 60% of patients treated with a single course of isotretinoin maintained remission over the long term. Some patients require multiple courses. Q. Are there any patients who are not likely to respond to this drug? Dr Leyden. My research has shown that preteens and young teenagers either respond poorly or have a high rate of clinical relapse. Most individuals with epithelial sinus tracts do not improve significantly. Women with excess androgen may clear initially, but then quickly relapse. Finally, patients with hemorrhagic or crusted lesions often worsen. They may develop pyogenic, granulomalike lesions or even acne fulminans. Q. Is there any alternative therapy for people who don't want to be exposed to isotretinoin's adverse effects? Dr Leyden. Women with intractable acne can choose hormonal therapy. Males don't have this option. They might have to rely on corticosteroid injections and/or standard therapy of topical retinoids with systemic or topical antimicrobials.

If a woman has evidence of hormonal irregularities, such as abnormal periods or hirsutism, she should undergo a full hormonal work-up, and the results can help guide the choice of hormone treatment. Systemic corticosteroid therapy can be useful for those who have excessive adrenal androgen production. For those with excessive ovarian androgen production, oral contraceptives containing estrogens or progestins are the best bet. Q. Don't some oral contraceptives have unwanted androgenic effects? Dr Leyden. New oral contraceptives with norgestimate or desogestrel have fewer androgenic effects. These include Ortho TriCyclen®, Ortho-Cept,® and Desogen®. Oral contraceptives are also appropriate acne therapy for women with normal menses who have no signs of excess androgen production. Q. What is the difference between severe acne and acne fulminans? Dr Leyden. Acne fulminans is abrupt in onset and is characterized by destructive inflammation. It is an uncommon variant of inflammatory acne and may also be accompanied by fever, leukocytosis, arthralgia, inflammatory bone lesions, and transient glomerulonephritis. The lesions can leave deep scars. Q. What kind of therapy is best for these patients? Dr Leyden. Acne fulminans usually responds to oral corticosteroids. Isotretinoin should not be used, as it may worsen the condition. Once the acute inflammation is controlled, isotretinoin can then be used. Q. Are there any other variants of inflammatory acne? If so, what's the best therapy for each? Dr Leyden. Pyoderma faciale refers to the acute appearance of numerous large pustules and furunculoid nodules. This condition usually arises in women on hormonal therapy or women who have undergone extreme emotional stress. It can be treated with isotretinoin. Pyoderma faciale and acne fulminans are fairly uncommon. Acne conglobata, however, is much less rare. Again, there is intense inflammation. Numerous deep, inflammatory nodules appear, some of which run together to form sinus tracts on the face and trunk. Scarring can be a problem, too. Isotretinoin is usually effective, though some patients may need to use systemic corticosteroids, either concomitant with or prior to isotretEditorial Director ......... Leo Orris, MD inoin. Managing Editor ............ Alison Marek

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Q. Is acne surgery ever warranted? Dr Leyden. I don't do it unless there are a large number of comedones, and even then I only do it after 1 to 2 months of topical retinoid therapy.

Graphic Design ............. Candy Hayes Production Manager ......... Laura Lynn Publisher ........................ Murray Stern

Acne Briefs is published under an unrestricted educational grant from Galderma. Editorial content does not necessarily reflect the opinions of the sponsor or the publisher. A publication of Academy Professional Information Services, Inc. 12 West 31st Street, New York, NY 10001 © Copyright 1999 Academy Professional Information Services, Inc.

ACNEBRIEFS · PAGE 7

ACNE BRIEFS REVIEW: UNDERSTANDING THE PATHOGENESIS OF ACNE

Summarized here are the key points made by James J. Leyden, MD, in his report on how understanding the pathogenesis of acne allows dermatologists to tailor therapy to patient needs.

Four Pathogenic Factors in Acne · Excessive secretion of sebum is a necessary prerequisite for the onset of acne. · Epithelial cells in the sebaceous follicles undergo abnormal desquamation. The combination of abnormally desquamated cells and excessive sebum form a microcomedo -- the precursor lesion of both noninflammatory comedones and inflammatory lesions. · The anaerobic bacterium Propionibacterium acnes proliferates in the lipid-rich environment of the microcomedo. · P acnes produces proinflammatory mediators and chemotactic factors that can cause microcomedones to inflame and evolve into papules, pustules, and nodules. Hormones in Acne · Most acne patients probably have sebaceous glands that are hypersensitive to the effects of androgens. · The most important hormones in the pathogenesis of acne are testosterone and dihydrotestosterone (DHT). · Women with signs of virilization may have excess androgen production and need to undergo a hormonal work-up. Topical Retinoids Render Follicles Inhospitable to P acnes · Topical retinoids such as adapalene (Differin®), or tretinoin (Retin-A®, Retin-A Micro TM, or Avita®) are the treatment of choice for normalizing follicular epithelial desquamation and making the environment less favorable for P acnes proliferation.

· The application of adapalene or tretinoin results in a "less plugged" follicle. · To achieve optimal results, topical retinoids should be used for several months. · Combination therapy with antibiotics, either topically or systemically, makes sense for most patients. Treating Acne · For mild inflammatory acne: daily applications of a topical retinoid along with a combination of benzoyl peroxide with erythromycin. · For mild to moderate inflammatory acne, either (1) adapalene or tretinoin with benzoyl peroxide, or (2) topical retinoids with a combination of benzoyl peroxide/erythromycin. · Depending on severity, some patients may need to use both an oral and a topical version of a single antibiotic. · Patients with large lesions can be treated with a local injection of a corticosteroid. · Patients with nodular, cystic lesions may respond to oral antibiotic therapy alone. Some may require the systemic retinoid isotretinoin. In women, hormonal therapy with or without spironolactone is another option. · For women with excessive ovarian androgen production, oral contraceptives containing estrogens or progestins are a good choice. · Acne fulminans usually responds to oral corticosteroids. · Acne surgery can be used if there are a large number of comedones, and the patient has applied topical retinoids for 1 to 2 months.

BIBLIOGRAPHY

Coates P, Adams CA, Cunliffe WJ, et al. Does oral isotretinoin prevent Propionibacterium acnes resistance? Dermatology. 1997;195(suppl 1):4-9. Leyden JJ. Therapy for acne vulgaris. In: Wood AJJ, ed. Drug therapy. New Engl J Med. 1997;336(16):1156-1161. Leyden JJ. Oral isotretinoin: how can we treat difficult acne patients? Dermatology. 1997;195(suppl 1):29-33. Strauss JS. Biology of the sebaceous gland and the pathophysiology of acne vulgaris. In: Soter NA, Baden HP, eds. Pathophysiology of Dermatologic Diseases. 2nd ed. New York, NY; McGraw-Hill, Inc. 1991:195-210. Thiboutot DM. Acne: an overview of clinical research findings. Dermatol Clin. 1997;15(1):97-109.

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