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C H A P T E R 1 5

Acne (Type 1

Sensitive Skin)

Leslie Baumann, MDJonette Keri, MD, PhD

ally associated with one another, with thelatter often succeeding the former.Inflammation of the follicular epithelium,which loosens hyperkeratotic materialwithin the follicle creating pustules andpapules, characterizes acnegenesis (Fig.15-1). Comedogenesis is best described asa noninflammatory follicular reactionmanifested by a dense compact hyperker-atosis of the follicle, and usually precedesacnegenesis. Because the etiology of suchlesions varies from person to person andwithin individuals also, it is difficult tocategorically identify or isolate a basiccause of acne; however, three principalfactors have been identified. The primarycausal factors in acne work interdepen-dently and are mediated by such impor-tant influences as heredity and hormonalactivity.

Sebaceous Gland Hyperactivity

Sebum is continuously synthesized bythe sebaceous glands and secreted to theskin surface through the hair folliclepore. The excretion of lipids by thesebaceous glands is controlled hormon-ally. The sebaceous glands are located allover the body but are largest and mostnumerous in the face, back, chest, andshoulders. These glands become moreactive during puberty because of the

increase in androgens, particularlytestosterone, which spurs sebum pro-duction. This imbalance between sebumproduction and the secretion capacityleads to a blockage of sebum in the hairfollicle followed by inflammation.

Hormones continue to affect seba-ceous gland activity into adulthood. Inmales, lipid secretion is regulated by theaction of testosterone. In females, theimmediate increase in luteinizing hor-mone following ovulation incites acceler-ation in sebaceous gland activity. Thehigher sebum secretion then stimulates orexacerbates acne breakouts usually 2 to 7days prior to menstruation. Women expe-riencing excessive androgen states, suchas those seen in polycystic ovarian dis-ease, frequently suffer from acne as well.

The notion that sebum plays a key rolein acnegenesis is buttressed by several factsincluding its comedogenicity, data showingthat it causes inflammation when injectedinto the skin, and the reportedly higherlevel of sebum production in people withsevere acne.6 Researchers have alsoreported that acne patients possess largersebaceous glands than the general popula-tion.7 Furthermore, drugs that inhibit seba-ceous gland activity, such as antiandro-gens, estrogens, and oral retinoids, areintegral treatment modalities in the suc-cessful control of acne.

Any discussion of the practice of cosmeticdermatology must include a discussion ofacne. Although acne is not typically con-sidered to be a “cosmetic” problem, itshighly visible nature makes it a very com-mon complaint among cosmetic patientswho are by definition concerned abouttheir appearance. Acne can often have aprofound psychological impact onpatients. Recently, an evaluation of thepsychosocial implications of acne on self-image and quality of life found that it maybe equivalent to disorders such as asthmaor epilepsy.1 Acne can be especially trou-blesome to adults who perceive them-selves as too old to have this conditionmost often associated with adolescence.

Acne vulgaris is a common, multifacto-rial process involving the pilosebaceousunit. More than 17 million people2 and75% to 95% of all teens3 are affected bysome form of acne each year in theUnited States alone. The majority ofpatients outside this age range are adultwomen who typically exhibit a hormonalcomponent to their acne. Approximately12% of women will have acne until theage of 44, whereas only 3% of men willhave acne until the same age.4 In manycases, adults are more surprised and upsetby acne onset than are teenagers. In allcases, though, early and individually tai-lored treatment is necessary to achieve asatisfactory cosmetic appearance for thepatient. This chapter will include a briefsurvey of the salient aspects of acnepathophysiology as well as suggestionsfor treatment and prevention. The psy-chosocial aspects of acne, or the signifi-cant psychological distress that this con-dition provokes, is beyond the scope ofthis chapter. It is worth noting, however,that many patients seeking treatmentonly for acne report substantial anxietyassociated with this disease. Regardless ofacne severity, acne is also one of the chiefconcerns of patients with body dysmor-phic disorder5 (see Chapter 40).

PATHOPHYSIOLOGY OF ACNE

Comedogenesis and acnegenesis are actu-ally discrete processes, but they are usu- � FIGURE 15-1 The hair follicle or “pore” is the site where acne occurs.

Sebaceous gland

Hair shaft

epidermis

dermis

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The literature reveals no discernibledifferences in the sebum composition ofacne patients as compared to age-matched controls. Strauss and Thiboutothave noted, though, an inverse relation-ship between sebum secretion andlinoleic acid concentration in the sebumof acne patients—the higher the sebumsecretion, the lower the linoleic acid con-centration.7 Downing et al. theorized thatthe lower concentrations of linoleic acid,which correlated with the high sebumsecretion rates of acne patients, leads to alocalized deficiency of essential fatty acidof the follicular epithelium.8 This defi-ciency then contributes to diminishedepithelial barrier function and follicularhyperkeratosis, which aggravates acne.

Changes in Follicular Keratinization

In the lower portion of the follicularinfundibulum, the normal process ofkeratinization occurs in the same waythat it occurs on the skin’s surface. Thismaturing of keratinocytes and subse-quent exfoliation into the follicle marksthe beginning of the formation of come-dones. In acne patients, these ker-atinocytes tend to stick togetherbecause of the effects of positive andnegative charges, the actions of transg-lutaminase, and the stickiness of sebum.The clumped keratinocytes block thepore/follicle, creating a blackhead if thepore is open (“open comedone”) or awhitehead if it is closed (“closed come-done”) (Fig. 15-2). The clogged pore is agreat nutritional source for bacteria soPropionibacterium acnes gravitate to theblocked pores. The immune system rec-

ognizes the presence of bacteria andmounts an immune response resultingin redness, pus, as well as inflammation,and the typical “pimple” results. Mostof the inflammation, however, is likelydue to inflammatory mediators that arereleased when bacteria digest sebum(Fig. 15-3).

The Influence of Bacteria

P. acnes has been cited as the cause ofacne because it is typically present inteenagers with acne and not those with-out acne.7 However, P. acnes is com-monly found in the facial flora of adultswith or without acne. The exact role ofbacteria is therefore unclear. It is knownthat sebum accumulation because ofexcess lipid secretion and hyperkeratosisat the infundibulum leads to an increasein P. acnes around the hair follicles. Thepresence of the bacteria is likely not adirect cause of acne breakouts, though. Itis more likely that the inflammation seenin acne is caused by free fatty acids thatresult from the breakdown of triglyc-erides in the sebum owing to bacteriallipases. Other extracellular enzymes,proteases, and hyaluronidases may alsoplay a role in the inflammatory process.7

The role of Toll-like receptors (TLRs)has been a recent topic of avid interestregarding the pathogenesis of acne.According to Heymann, these trans-membrane proteins, when activated byligands, modulate the expression ofnumerous immune response genes.9

Evidence suggests that P. acnes, throughits several secreted proinflammatoryproducts, can induce TLR expression

with resultant acne inflammation.In vitro work on monocytes has shownthat all-trans-retinoic acid led to down-regulation of TLR2, yielding moredetails regarding the retinoid mecha-nism of action10 (see Chapter 4).

DIFFERENTIAL DIAGNOSIS

There are several acne variants and disor-ders with similar presentations. A briefsurvey of these conditions appears nearthe conclusion of this chapter. In addi-tion, many other dermatologic condi-tions can be confused with acne (Box 15-1). These are unrelated conditions, butcan be mimics.

The Basic Lesion

The fundamental acne lesion is themicrocomedo, or microcomedone, anenlarged hair follicle full of sebum and P. acnes. Although there is a long list ofmaterials that can cause comedones, themechanism of spontaneous comedoneformation is unknown.11 The comedothat remains beneath the skin is a white-head; a comedo that opens to the surfaceof the skin is labeled a blackhead becauseit appears black on the epidermis. Thediverse array of other acne lesionsincludes papules (small, inflamed lesionspresenting as pink, tender, nonpustularbumps); pustules (small, inflamed, ten-der, pustular lesions, usually red at thebase); nodules (relatively large, spherical,painful lesions located deeper in the der-mis); and cysts (even deeper, inflamed,pustular, painful lesions that can causescarring) (Figs. 15-4 and 15-5).

TREATMENT

There are several therapeutic regimensfor acne, most of which focus on pre-vention of future eruptions rather thantreatment of present lesions. This is thereason that the majority of treatmentstake 8 weeks to work. Only salicylic acid,benzoyl peroxide, and steroids treat lesionsalready visible on the skin. Steroids,

� FIGURE 15-2 Open comedones and inflammatory papules on the neck.

BOX 15-1 Conditions That Can Be

Confused with Acne

Adenoma sebaceum

Keratosis pilaris

Perioral dermatitis

Pityrosporum folliculitis

Rosacea

Seborrheic dermatitis

Steroid abuse/use dermatitis

Tinea barbae

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although frequently used, are notadvised because they can lead to“steroid acne.” Five basic principles gov-ern the successful treatment of acne:

The Five Steps

NORMALIZING KERATINIZATION/EXFOLIATION

The first step in controlling acne is toprevent the exfoliated keratinocytes

from sticking together (Box 15-2).Retinoids achieve this goal by reducingthe positive and negative charges thatrender the cells sticky and by decreasingthe levels of transglutaminase—anenzyme responsible for cross-linking cellmembrane proteins of the keratinocytes.In fact, tretinoin has been said to have“superior ability to eradicate existingcomedones and prevent the formation of

Sebaceousgland

Cellcycle

Sloughed cells

Sebum

Desquamatedcells clog follicle

Bacteriamoves in

Pus, bacteriaand cells Rupture of follicle wall

Bacteria,inflammation

A

C

D

E

B

� FIGURE 15-3 A close-up of the hair follicle and sebaceous gland demonstrating the different stages of acne. A. Desquamation of ker-

atinocytes occurs in the same way that it does on the skin’s surface. However, instead of sloughing into the environment, the keratinocytes

slough into the hair follicle. This is a continuous and normal process that represents the culmination of the cell cycle. B. The first stage of

acne is also known as comedogenesis. The sloughed cells stick together inside the hair follicle, resulting in a clogged pore or comedone.

This is caused by several factors including increased amounts of sebum, inflammation of the sides of the hair follicle preventing the release

of the desquamated keratinocytes, and inceased cohesion of keratinocytes. C. The keratinocyte plug and sebum is an excellent food source

for bacteria. The bacteria invade the comedone and release inflammatory factors that lead to the next stage of acne. D. Inflammation con-

tinues with increased redness and pus. This is clinically detectable as a papule or pustule. E. Continued inflammation may lead to so much

inflammation that the hair follicle ruptures and the bacteria and debris are released into the dermis. When severe, this can lead to scarring.

BOX 15-2 Products That Block Step 1

(Retinoids)

Tretinoin (Avita™, Renova™, Retin-A™,

Retin-A Micro™, Atralin™)

Adapalene (Differin™)

Tazarotene (Tazorac™)

Retinol, retinyl linoleate, retinyl palmitate

Oral retinoids: isotretinoin (Accutane™,

Claravis, Sotret, Amnesteen)


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new ones.”12 Ultrastructural studiesexamining tretinoin use have demon-strated the loosening of follicularimpactions and loss of cohesivenesswithin microcomedones.13 Tretinoinshould be considered a first-line therapyfor acne because it renders theunplugged follicle more accessible to thepenetration of antibiotics.12

Patients with cystic acne, or thosewho are unresponsive to all otherregimens, can be treated with oralretinoids such as isotretinoin (Fig. 15-6).This is the only class of drugs that nor-malize keratinization as well as reducesebaceous gland function. It has beenshown that a marked decrease in sebumproduction occurs within 2 weeks of the

BOX 15-3 Products That Affect Step 2

Topical antibiotics: clindamycin, erythromycin

solution

Combination products with benzoyl peroxide

and either clindamycin or erythromycin

Benzoyl peroxide

Azelaic acid (Azelex™)

Sodium sulfacetamide

Sulfur

Oral antibiotics

Light Therapy

� FIGURE 15-4 Multiple papules and pustules in an acne patient.

� FIGURE 15-5 Acne on the chin. Patients with this presentation should be asked if they are plucking

or waxing hairs on the chin because this distribution mimics folliculitis.

onset of therapy.14 All oral retinoidshave teratogenic effects and patientsshould be cautioned to avoid pregnancywhile taking these medications.

ELIMINATING OR REDUCING P. ACNES

BACTERIA The use of antibiotics orbenzoyl peroxide attacks the bacterialpopulation thereby decreasing the levelof inflammatory extracellular productsinduced by P. acnes (Box 15-3). The twoantibiotics that are most commonlyused in the treatment of acne, and havebeen shown to be equally effective,15 areerythromycin and clindamycin. In addi-tion to being antibacterial, these agentsexhibit anti-inflammatory activity asthey lower the percentage of inflamma-tory free fatty acids produced by bacter-ial digestion of surface lipids.16

The escalating incidence of antibioticresistance is also an important considera-tion when treating the bacterial aspect ofacne. Recent research suggests that asmany as 60% of acne patients exhibitantibiotic-resistant strains of P. acnes.17 Arecent review of 50 controlled trials foundthat there was a gradual decrease in theefficacy of topical erythromycin, but thatthe efficacy of topical clindamycin stayedthe same.17 The preponderance of bacte-ria remain sensitive to medication in mostof these patients, but an increasing num-ber of patients have gradually developedless sensitive or more resistant strains.Regardless, the use of two modalities (i.e.,benzoyl peroxide and a topical antibiotic)in acne therapies has been shown todecrease the resistance.

Although standard dosing regimensof oral antibiotics remain a mainstayof treatment, newer lower-dose antibi-otic formulations represent submicro-bial dosing and again are seen as aprudent approach to combating bacte-rial resistance. With such low-doseantibiotics, the drug works as an anti-inflammatory agent rather than anantimicrobial.

Benzoyl peroxide kills bacteria bygenerating reactive oxygen species in


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the sebaceous follicle.18 Because itcauses free radical formation, the use ofbenzoyl peroxide may lead to exagger-ated or accelerated aging of the skinand its use should be avoided. Whenapplied at the same time as topicaltretinoin, benzoyl peroxide can dena-ture the tretinoin and reduce its effec-tiveness.19

Sodium sulfacetamide and sulfur arepresent in a variety of combination prod-ucts. Sodium sulfacetamide is an antibac-terial agent, and the mechanism of actionof sulfur is also thought to be antibacter-ial in addition to being keratolytic.

REMOVING THE MATERIAL THAT CLOGS THE

PORES Comedolytics, such as salicylicacid (BHA) and AHAs, are used to loosenthe keratinocytes and “unclog” the pores(Box 15-4). BHA is more effective inreducing the number of comedones thanare AHAs (see “AHAs versus BHA”).Comedone extractions and “acnesurgery” can also be performed.

ATTACKING THE INFLAMMATORY RESPONSE

The use of anti-inflammatory products,such as salicylic acid, is an effectiveapproach to the most physically trouble-

some symptom of acne (Box 15-5). Steroidinjections and topical corticosteroids,especially potent topical corticosteroids,pose important risks such as steroid atro-phy and steroid acne. However, in severecystic, scarring acne, oral corticosteroidsand intralesional steroids may be war-ranted and necessary to prevent scarring.Finally, in-office BHA peels are effectivein reducing the inflammation seen in acne(Table 15-1).

DECREASING THE LEVEL OF SEBUM The useof oral and topical retinoids decreasessebaceous gland activity. Hormonal sta-bilization, using oral contraceptives, isalso an effective way for females toreduce sebaceous secretions (Box 15-6).Although there are currently only threeoral contraceptive pills approved by theFDA in the United States for the treat-ment of acne (i.e., Ortho Tri-cyclen,Estrostep, and Yaz), other such pills canbe used. Yaz, which was recentlyapproved, is a combination product ofethinyl estradiol and drospirenone. Thedrospirenone in this product is an antian-drogen and has about the same antian-drogen effect as 25 mg of spironolactone.Yaz and Yasmin, other oral contracep-

TABLE 15-1

Anti-inflammatory Agents

Aloe vera

Chamomile

Coenzyme q10

Cucumber extract

Feverfew

Green tea

Licorice extract

Mushrooms

Niacinamide

Pycnogenol

Silymarin

� FIGURE 15-6 Cystic acne on cheeks.

AHAs versus BHA

There is a significant chemical distinction

between salicylic acid and the alpha

hydroxy acids. The AHAs are water solu-

ble, while salicylic acid is lipid soluble.

Consequently, the distinct hydroxy acid

families enter and function in different

areas of the skin; salicylic acid usually

effects change only in the upper epider-

mis while AHAs are believed to penetrate

the dermis.20,21 This difference might

account for the longer duration of stinging

reported by patients using AHAs as com-

pared to those using BHA.

Because BHA is lipophilic, it is suited, unlike

AHAs, to penetrate the sebaceous material

in the follicles and thus able to induce

exfoliation within the infundibula.22 The

comedolytic properties of BHA were con-

firmed in a study in which investigators

compared the number of microcomedones

observed in biopsies of women treated with

2% salicylic acid to those in women treated

with 8% glycolic acid.23 The glycolic formu-

lation did not reduce the density of micro-

comedones, whereas BHA application

resulted in a statistically significant (p <0.05) decrease. Salicylic acid is marketed to

patients in a variety of formulations includ-

ing gels, lotions, masks, and cleansers.

Because of its anti-inflammatory activity,

salicylic acid is also widely used in acne

peels. A 1995 clinical study by Di Nardo

showed that a product containing a com-

bination of glycolic and salicylic acids

reduced more inflammatory acne lesions

than did benzoyl peroxide.24 It is notewor-

thy that this study demonstrated that the

combination of the AHA and BHA was

more effective against acne lesions than

was salicylic acid alone.

Anecdotally, salicylic acid has been reported

to work better than AHAs in the treatment

of rosacea because the anti-inflammatory

properties of BHA induce less erythema.

As of the date of this publication, however,

there have been no double-blind studies

to address this purported benefit.


Retinoids

Salicylic acid (BHA)

Alpha hydroxy acids (primarily glycolic

and lactic)

Azelaic acid


Salicylic acid (OTC acne wash, lotion, gel,

mask)

In-office BHA peels

Oral NSAIDs


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tives, are similar in that both containdrospirenone, but differ in the amount ofestrogen, with Yaz being the lower estro-gen pill. (For a more detailed discussionon the effects of hormones on the skin,see Chapter 5.)

MOISTURIZATION AND ACNE

In 1980, Swinyer reported on the differ-ences between treating acne patients ina climate with relatively normal humid-ity in comparison to treatment in a dryclimate. He identified skin dryness as animportant factor in exacerbating thepathogenetic cycle of acne, thus ham-pering its treatment.25 In a subsequentfour-cell study that tested Swinyer’shypothesis, Jackson et al. conducted a 3-month evaluation of the influence ofcleansing regimens on the effectivenessof acne therapy using 10% benzoylperoxide lotion, isolating the type ofcleanser as the only variable. Anemollient facial wash clearly outper-formed pure soap and a benzoyl perox-ide wash in decreasing open come-dones, papules, and in overall globalassessment.26 (Soap and placebo com-prised one cell of the study; in each ofthe others, the variable—soap, an emol-lient, or benzoyl peroxide wash—wasmatched with 10% benzoyl peroxidelotion.)

Washing the skin with a noncomedo-genic agent appears to act against acneand serves as a suitable alternative tocleansing with relatively abrasive prod-ucts while satisfying the acne patient’stypical desire to wash one’s face. Inhydrating while cleansing, use of anemollient facial cleanser will acceleratethe pace of acne resolution and con-tribute to overall response regardless ofthe patient’s treatment regimen.26

ACNE PREVENTION REGIMEN

Regimens should contain products thataffect each of the five steps of acne for-mation described above. One such pro-gram is the following:

AM

1. Washing with a mild 2% salicylicacid cleanser.

2. Applying a topical antibiotic solutionor azelaic acid.

3. Applying a sunscreen SPF 45 withmoisturizing cream (unless the skin isvery oily, in which case the patientshould try a lotion or gel).

PM

1. Washing with the same salicylic acidcleanser.

2. Applying a topical retinoid.

The physician might consider addingin-office salicylic acid peels, oral antibi-otics and retinoids, and oral contracep-tives in recalcitrant cases. Some make upfoundations contain salicylic acid as anadditive to aid in the prevention or ame-lioration of acne.

COMMON ACNE VARIANTS

Acne Cosmetica

Developing acne as a result of cosmeticsuse is not as common today as it was just a couple of decades ago.Manufacturers test their products forcomedogenicity now before puttingthem on the market. So, if a personchooses nongreasy, nonocclusive prod-ucts, the cosmetic choice is unlikely tobe a source of acne. See Chapter 32 formore information.

Acne Detergicans

The obsessive use of soaps by patientsmay lead to acne. Many facial cleansersand shampoos contain unsaturated fattyacids that have been shown to be come-dogenic.27 Other components such asbacteriostatic agents and botanicalingredients may irritate the hair follicleand cause acne as well. Therefore, it isimportant to educate patients thatwashing does not necessarily improveacne because the detergents used areonly capable of removing surface oil anddo not affect the sebum in the follicles,where the disease originates. (Of course,one exception to this would be cleanserscontaining salicylic acid, which has beenshown to penetrate into the comedonesand improve them.) Acne detergicans isuncommon but should be considered inpatients that wash their face or skinmore than 4 times daily.28

Rosacea

This is an acneiform condition typicallypresenting in adults between 25 and 60years of age that is characterized byfacial redness, flushing, papules and pus-tules, and the formation of prominentblood vessels in the face. These patientsusually worsen with AHAs and

retinoids but do well with antibiotics,BHA, and laser treatment of telangiec-tasias. The exact cause is unknown, butrosacea is a condition distinct from acne,although a patient may have both condi-tions at the same time (see Chapter 16).

SUMMARY

The pilosebaceous unit, which com-prises the hair follicles, the cells that linethem, and nearby sebaceous glands, isthe location where acne manifests. Thisdisease is a function of a complex inter-play of hereditary, hormonal, and occa-sional exogenous factors. A change inthe inner lining of the hair follicle—cellsturn over too quickly and clumptogether—results in an inhibition of theusual passage of sebum and a blockageat the follicular opening. This sets thestage for the involvement of P. acnes andsubsequent inflammation.

Just as the etiology is complex andmultifactorial, the approach to treat-ment is variable and requires severalsteps tailored to the individual patient.There is not, to date, one isolated causeor a panacea—a medication that worksfor all patients. Early intervention andpreventative treatment are largely effec-tive in resolving all but the most recalci-trant cases of this common, cosmeticallyaltering, and distressing condition.

REFERENCES

1. Thomas DR. Psychosocial effects ofacne. J Cutan Med Surg. 2004;8(suppl 4):3.

2. Health Topics Questions and AnswersAbout Acne: NIDDK. http://www.wrongdiagnosis.com/artic/health_topics_questions_and_answers_about_acne_niddk.htm. Accessed January 25, 2008.

3. Cordain L, Lindeberg S, Hurtado M, et al. Acne vulgaris: a disease of Westerncivilization. Arch Dermatol. 2002;138: 1584.

4. Goulden V, Stables GI, Cunliffe WJ.Prevalence of facial acne in adults. J AmAcad Dermatol. 1999;41:577.

5. Bowe WP, Leyden JJ, Crerand CE, et al.Body dysmorphic disorder symptomsamong patients with acne vulgaris. J AmAcad Dermatol. 2007;57:222.

6. Harris HH, Downing DT, Stewart ME,et al. Sustainable rates of sebum secre-tion in acne patients and matched normalcontrol subjects. J Am Acad Dermatol.1983;8:200.

7. Strauss JS, Thiboutot DM: Diseases ofthe sebaceous glands. In: Freeberg I,Eisen A, Wolff K, et al., eds. Fitzpatrick’sDermatology in General Medicine. 5th ed.New York, NY: McGraw-Hill; 1999:769.

8. Downing DT, Stewart ME, Wertz PW,et al. Essential fatty acids and acne. J AmAcad Dermatol. 1986;14:221.

9. Heymann WR. Toll-like receptors in acnevulgaris. J Am Acad Dermatol. 2006;55:691.


Oral contraceptives

Retinoids (see Step 1)


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10. Liu PT, Krutzik SR, Kim J, et al. Cuttingedge: all-trans retinoic acid down-regu-lates TLR2 expression and function. JImmunol. 2005;174:2467.

11. Webster GF. Acne vulgaris: state of thescience. Arch Dermatol. 1999;135:1101.

12. Berson DS, Shalita AR. The treatment ofacne: the role of combination therapies. JAm Acad Dermatol. 1995;32:S31.

13. Lauker RM, Leyden JJ, Thorne EG. Anultrastructural study of the effects of top-ical tretinoin on microcomedones. ClinTher. 1992;14:773.

14. Farrell LN, Strauss JS, Stranieri AM. Thetreatment of severe cystic acne with 13cis-retinoic acid: evaluation of sebumproduction and the clinical response in amultiple-dose trial. J Am Acad Dermatol.1980;3:602.

15. Thomas DR, Raimer S, Smith EB.Comparison of topical erythromycin1.5% solution versus topical clin-damycin phosphate 1% solution in

the treatment of acne. Cutis. 1982;29:624.

16. Esterly NB, Furey NL, Flanagan LE. Theeffect of antimicrobial agents on leuko-cyte chemotaxis. J Invest Dermatol.1978;70:51.

17. Simonart T, Dramaix M. Treatment ofacne with topical antibiotics: lessonsfrom clinical studies. Br J Dermatol. 2005;153:395.

18. Nacht S, Young D, Beasley JN, et al.Benzoyl peroxide: percutaneous absorp-tion and metabolic disposition. J Am AcadDermatol. 1981;4:31.

19. Martin B, Meunier C, Montels D, et al.Chemical stability of adapalene andtretinoin when combined with benzoylperoxide in presence and in absence ofvisible light and ultraviolet radiation. Br JDermatol. 1998;139(suppl 52):8.

20. Draelos Z. Hydroxy acids for the treat-ment of aging skin. J Geriatric Dermatol.1997;5:236.

21. Brackett W. The chemistry of salicylicacid. Cosmet Dermatol. 1997;10(suppl):5.

22. Davies M, Marks R. Studies on the effectof salicylic acid on normal skin. Br JDermatol. 1976;95:187.

23. Kligman A. A comparative evaluation of anovel low-strength salicylic acid creamand glycolic acid. Products on human skin.Cosmet Dermatol. 1997;10 (suppl):S11.

24. Di Nardo J. A comparison of salicylicacid, salicylic acid with glycolic acid andbenzoyl peroxide in the treatment ofacne. Cosmet Dermatol. 1995;8:43-44,14.

25. Swinyer LJ, Swinyer TA, Britt MR. Topicalagents al one in acne. JAMA. 1980;243:1640.

26. Jackson EM. The effects of cleansing inan acne treatment regimen. CosmetDermatol. 2000;12(suppl):9.

27. Kligman A, Wheatley V, Mills O.Comedogenicity of human sebum. ArchDermatol. 1970;102:267.

28. Mills O, Kligman A. Acne detergicans.Arch Dermatol. 1975;111(1):65.

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