cliniraICORNERSTONE 1 OFFICE DERMATOLOGY I Vol 4 No I
`
`Acne Vulgaris and Rosacea:
`
`Evaluation and Management
`
`Guy F. Webster, MD, PhD
`Professor and Vice Chairman for Clinical Affairs
`
`Department of Dermatology and Cutaneous Biology
`Director. Center for Cutaneous Pharmacology
`Thomas Jefferson University
`Philadelphia, Pennsylvania
`
`Acne vulgaris, commonly termed acne, is an extremely common disease. It can be found in nearly all
`teenagers to some degree as well as in women in their 30s. Regardless of severity, acne often has a
`greater psychologic effect than cutaneous effect. Indeed, most patients overestimate the severity of their
`disease, while most physicians underestimate its impact on their patients. Studies have shown that peo-
`ple with severe acne as teens are less employable as adults and that self-esteem is low. When combined
`with other adolescent tensions, acne can be a difficult disease to treat. Rosacea, which usually starts in
`the late 20s, may affect the eyes as well as the skin. This article describes the pathogenesis of acne and
`rosacea and treatment approaches the primary care physician can use.
`
`PATHOGENESIS
`OF ACNE VULGARIS
`
`The pathogenesis of acne vulgaris is multifacton'al,
`involving disturbances of keratinization, hormonal
`secretion, and immunity (Table I). The central
`defect involves the formation of the comcdo, a plug
`in the follicle that results from aberrant dcsqua-
`malion of the follicular wall. Clinically. comcdones
`are described as “open" if the pore is visible and
`“closed” if it is not. The black tip of an open come-
`do results from the oxidation of sebaceous lipid and
`melanin and is not dirt, contrary to advice from
`mothers throughout the world. The cause of come—
`do formation is not known.
`It is Clear that come—
`
`dones do not result from poor hygiene, diet, or use
`of brand—name cosmetics.
`In fact, major cosmetic
`
`companies test their products for acncgenicity.
`In many patients acne remains for the most
`part in this first stage; in others it progresses to
`inflammatory lesions of varying severity (Table II).
`The target of inflammation is Propionibacterium
`acnes, an aerotolerant anaerobic member of the
`normal flora in sebaceous regions of the skin.
`
`P acnes lives in the follicle and metabolizes seba—
`
`ceous triglycerides into fatty acids and glycerol.
`It consumes the glycerol and casts off the fatty
`
`In the past it was thought that the fatty acids
`acids.
`in sebum were the cause of acne inflammation;
`
`however, research has shown that the organism
`itself is the target.
`P acnes is highly inflammatory, activating
`complement, secreting neutrophil and monocytc
`chcmotactic factors, activating lymphocytes, and
`inducing lysosomal enzyme release. The organism
`degrades slowly, resulting in a persistent follicular
`inflammatory response.
`
`
`
`'Th- ceinfi'al defect: in he. thes th'
`formation of thatcomedqaplugIn
`the inflicted-tat 'ms'titu ir’q'm abet-mm.
`desquamation ofthefollicularstall.
`
`

`

`clinitnlCORNERSTONE I OFFICE DERMATOLOGY I Vol.4 No.l
`
`TABLE I.
`
`PATHOGENESIS OF ACNE
`
`Follicular dyskeratinization —> Comedo formation
`
`Androgen secretion —) Sebum production —-) Propionibacten'um acnes proliferation
`Hypersensitivity to P acner ——> Increased severity of inflammation
`
`TABLE II.
`
`TYPES OF ACNE LESIONS
`
`Comedo—Lesions may be “open" or "closed," depending on the presence of a visible black tip resulting from
`defective keratinization.
`
`Papule/pustule—Inflammatory lesions that if large or persistent may lead to permanent scarring.
`
`Nodule—A deep inflammation. >5 mm in size, guaranteed to produce a scar. Lesions are erroneously termed
`“cysts." In reality, they are abscesses Willi no cyst wall present.
`
`Conglobale lesions—Grouped nodules connected by sinus tracts present in the severest forms of acne.
`
`Because all individuals have a significant
`level of P acnes and some degree of follicular
`plugging, it is curious that we all do not have active
`acne. The explanation lies in the level of the
`immune response to the organism. Patients with
`excessive humoral and cellular immunity to
`P acnes mount a more destructive inflammatory
`
`response that produces clinical lesions. This
`response may represent a true hypersensitivity to
`P cones in that the organism is a beneficial com—
`mensal and of minimal infectious potential.
`
`
`
`A minority of women have an endocrine
`
`aspect to their acne. Although not necessarily
`severe, their acne may be refractory. Such patients
`may have a history of irregular menses, be over—
`weight, or have increased facial hair or andro-
`genetic alopecia.
`There are many acne grading systems. Those
`
`day clinical setting. A practical approach is for the
`physician and patient to reach some consensus on
`how bad the acne is by looking at the severity of the
`actual lesions and the impact of the disease 0n the
`patient. Inflammatory acne lesions range in severity
`from superficial pustules to deep scarring nodules
`(Table II). Generally, patients will have a mixture
`of lesion types, and their acne should be graded
`
`based on the most severe lesions present; that is, a
`patient with 3 scarring nodules has more severe
`acne than a patient with 50 superficial pustules.
`The presence of acne on the chest or back also con-
`notes a more severe and hard-to-treat disease.
`The terms inverse acne. triad acne, and
`
`hidradenitis suppurativa all describe a follicular
`process that results in comedo formation and
`In the
`inflammation in the scalp, axilla, and groin.
`past this process was thought to be an apocrine dis-
`ease, but recent thought holds it to be a disease of
`the hair follicle, like acne vulgaris. However,
`unlike acne vulgaris, P acnes plays little or no role
`in acne of nonsebaceous regions. Various bacteria,
`enterics, pseudomonads, and streptococci colonize
`these lesions and provoke inflammation and sear—
`ring. Sinus tract formation is common and results
`in disease that is often best treated surgically.
`
`systems that involve pimple counting are useful in.
`clinical trials but are too cumbersome in the every-
`
`Treatment Approaches
`The first step in the treatment of a patient with acne
`
`

`

`clinicalCORNERSTONE - OFFICE DERMATOLOGY ' Vo|4 N0.|
`
`TABLE III.
`
`.
`
`TOPICAL ACNE THERAPY
`
`Anticamedonal
`
`O Tretinoin
`
`O Tazarotene
`
`0 Adapalene
`
`0 Salicylic acid
`
`Antibacterial
`
`O Azelaic acid
`
`O Benzoyl peroxide
`
`O Erythromycin
`
`0 Clindamycin
`
`O Benzoyl peroxide/erythromycin gel
`
`0 Benzoyl peroxide/clindamycin gel
`
`Anti-inflammatory
`
`0 Sodium sulfacetamide
`
`TABLE IV.
`
`ORAL ACNE THERAPY
`
`Antisebaceous, Anticomedonal,
`
`Antibiotics
`Antiandrogen
`Anni-inflanunamry
`
`O Tetracycline (250—1000 mg qd in divided dose)
`
`0 Oral contraceptives
`
`0 Isotretinoin (0.5—2 mg/kg per day)
`
`0 Doxycycline (50—200 mg qd in divided dose)
`
`0 Spironolactone
`
`O Minocycline (50—200 mg qd in divided dose)
`
`0 Erythromycin (250—1000 mg qd in divided dose)
`
`W i
`
`s to be certain that the patient (and the parents if
`the patient is an adolescent) have not fallen prey to
`the numerous myths about the disease. Acne is not
`caused by dirt, diet, or impure thoughts. Patients
`commonly believe that one particular food, usually
`a greasy or sweet one, worsens their acne. Hair
`falling on the forehead does not cause pimples, and
`the disease cannot effectively be treated with soap
`and water. Popping pimples is bad—it promotes
`scarring and prolongs the life of many lesions.
`Stress may play a role but tranquilizers have no
`positive effect on acne.
`Physicians and patients must communicate
`particularly well during the treatment of acne. The
`first visit is very important in that patients can be
`given realistic expectations and be disabused of
`incorrect ideas. Teens in particular expect quick
`results; however, they need to understand that 3 to 6
`weeks is the quickest that acne can be expected to
`improve. Bigger lesions may take longer as do open
`comedones. For many patients any mark on the face
`after a pimple heals is considered a scar and they
`need to understand the distinction between true scars
`and transient postinflammatory pigment changes.
`
`There is wide variation in acne regimens.
`Some physicians use I or 2 drugs in each patient
`while others use 5 or 6. In general 1 or 2 properly
`chosen drugs do better and are easier for the patient
`to comply with than a more complex regimen.
`Treatment may be topical (Table III) or oral (Table
`IV). Typical acne regimens are outlined in Table V.
`
`
`
`The central lesion in both comedonal and
`inflammatory acne is the microcomedo; therefore,
`most effective regimens include a retinoid such as
`tretinoin or tazarotene.
`Indeed, if one is sufficiently
`patient, topical retinoids are excellent monotherapy
`for all but the most severe acne. Because topical
`retinoid monotherapy takes several months to clear
`inflammatory acne, it is prudent to add a drug that
`
`

`

`clinical CORNERSTONE I OFFICE DERMATOLOGY I Vol.4 No!
`
`TABLE V.
`
`TYPICAL ACNE REGIMENS
`
`I Benzoyl pcroxidelerythromycin gel
`0 Topical retinoid + benzoyl peroxide
`0 Azelaic acid + benzoyl peroxide
`0 Topical reti noid + oral tetracycline/doxycyclinc/minocycline
`O Isotretinoin
`
`reduces inflammation by reducing P acne: popula-
`tions. Purely noninflammatory (comedonal) acne
`is the mildest form of the disease but can be the
`
`hardest to treat. Comedones are usually firmly
`ensconced in the follicle and left untreated cannot
`
`be easily expressed. Tretinoin (vitamin A acid)
`cream is the standard against which all other anti-
`comedonal agents are compared. It inhibits comedo
`formation and eliminates comedonal acne in a few
`
`months. The only significant side effect is irrita-
`tion, which is greatest after a few weeks and usually
`does not require intervention. A moisturizing lotion
`may be prescribed. Because their skin is inherently
`irritable, patients with atopic diseases may not toler—
`atc topical retinoids even with moisturization.
`Other drugs are also useful for inflammatory acne.
`Adapalene is a naphthoic acid derivative that binds
`to nuclear retinoid receptors and has retinoid
`etfects. It is effective for comedonal acne and has a
`
`measure of anti—inflammatory activity. It is roughly
`
`
`
`equivalent to topical tretinoin, but is somewhat less
`imitating. Tazarotene is a potent anticomedonal
`retinoid cream that is only slightly more irritating
`than tretinoin. Azelaic acid is a dicarboxylic acid
`that has both antibacterial and comedolytic effects.
`
`Topical application of this drug is fairly effective in
`reducing comedones. and it is the least irritating of
`the preparations. The side effect of hypopigmenta—
`tion may be desirable in some patients.
`
`In the past 10 or so years most dermatolo-
`gists have observed a decrease in the efficacy of
`topical erythromycin and clindamycin. This
`decrease is due to a dramatic increase in P acnes
`
`resistance to the drugs. Fortunately, the resistance
`does not translate into hard-to-treat infections, just
`hard-to-treat acne. The solution is to use the drugs
`only in conjunction with benzoyl peroxide, which
`effectively prevents the acquisition of resistance.
`Oral antibiotics that are effective in the treat-
`
`ment of acne include erythromycin, tetracyclines,
`trimethoprim-sulfamethoxazole, and ciprofloxacin.
`Because of concerns about the generation of a re-
`sistant gastrointestinal flora1 the latter 2 drugs are re—
`served for problematic cases. Tetracycline antibiotics
`have the advantage of additional anti-inflammatory
`activity in acne and are the most widely prescribed
`agents. Of the tetracycline antibiotics. doxycycline
`and minocycline have the most beneficial effects on
`acne and are well tolerated and safe.
`
`Because of the clear link to androgens, acne is
`
`often thought of as a hormonal disease, but it is unusu-
`al for a hormonal drug to be effective as monotherapy.
`Occasionally it is useful to add hormonal therapy to an
`acne regimen for women. TWO types of drugs may be
`used, oral contraceptives and spironolactone. Although
`only 2 oral contraceptives are currently approved for
`marketing as an acne treatment, it is likely that most
`are helpful in acne to a degree.
`How does one treat acne during pregnancy?
`
`Tetracyclines may cause staining of teeth and bones
`and is contraindicated. Although commonly per-
`ceived as a teratogen, topical tretinoin does not
`raise circulating vitamin A levels and does not
`result in fetal deformity. Nevertheless, many
`
`patients and physicians want to avoid worries and
`the drug is usually not prescribed during pregnancy.
`Benzoyl peroxide, azelaic acid, and oral cry-
`
`

`

`thromyein are considered to be safe for use during
`pregnancy; however, since nausea and heartburn are
`common during pregnancy, crythromyein should
`probably not be administered and the acne should
`be treated topically.
`
`
`
`A word must be said about topical steroids in
`the treatment of acne—don't. Topical steroids will
`actually cause acne and invariably atrophy of facial
`skin if used for any length of time. Intralesional
`triamcinolone acetonide is useful to calm large nod-
`ules but can cause pitting and hypopigmentation,
`both of which will eventually resolve. Commonly
`used is 0.05 mL of a 2-mg/mL dosage.
`Nodular, scarring acne that resists oral antibi—
`otics and topical retinoids is usually treated with
`oral isotretinoin. Isotretinoin is a potent therapy for
`severe acne. If treated with 1 mg/kg per day for 4
`to 6 months, most patients have little or no disease,
`and 80% have complete long-term remission and
`possibly cure of the disease. Unfortunately, isotret—
`inoin has significant side effects. There is an initial
`flare of acne in many patients that can be blunted by
`beginning at a low dose (eg, 20 mg) and then
`increasing to ~1 mg/kg after 1 month. Patients with
`truncal acne may have a particularly severe flare of
`disease. These patients are usually started on 20 mg
`of isotretinoin along with 20 mg of prednisone for
`the first month. The drug also produces dry skin
`and mucosae, elevated triglycerides in about 30% of
`patients, and occasional muscle or joint aches.
`Transaminase levels are occasionally elevated, but
`
`investigation usually determines that this elevation is
`muscle-derived rather than of hepatic origin.
`Recently there has been much public concern
`expressed about depression caused by isotretinoin.
`
`clinical CORNERSTONE I OFFICE DERMAYOLOGY I Vol 4 Nu!
`
`Large studies have failed to show a correlation
`between isotretinoin and mental illness. Discuss
`
`the use of isotretinoin with patients and parents if
`appropriate and agree to discuss any problems that
`may arise during usage. The more important issue
`is teratogenicity. This drug when taken orally pro—
`duces a high rate of miscarriage and babies born
`with deformity; therefore pregnancy must be rigor—
`ously avoided. Fortunately isotretinoin is rapidly
`eliminated, and female patients may conceive safe-
`ly 1 full menstrual period after stopping the drug
`
`ROSACEA
`
`Rosacea is a chronic adult skin disorder affecting
`both the skin and the eye. Rosacea usually starts in
`the late 205. It is most common in fair—skinned per-
`sons, especially those with a history of facial rubor.
`Some patients express only persistent redness and
`telangiectases; others develop sebaceous overgrowth
`(rhinophyma), inflammatory papules, or nodules.
`Lesions are most numerous on the central face.
`
`Approximately 50% of rosaeea patients have ocular
`involvement, which may manifest as irritation,
`styes, chalazia, and corneal damage. Ocular disease
`severity bears no relation to skin disease severity.
`The cause of rosaeea is uncertain. Vascular
`
`reactivity is certainly a predisposing factor. but it is
`not known why some patients develop sebaceous
`hyperplasia and others develop pimples. The nor—
`mal flora mite Demodexfolliculorum has been
`implicated, but no studies exist to confirm the sus»
`picion. Gastric disease caused by Helicobacter
`species was once implicated but now has been dis-
`proved as a cause of rosaeea.
`Topical drugs that are helpful in treating
`rosaeea include metronidazole, azelaic acid, and
`sodium sulfacetamide; however, response may take
`Weeks to be apparent. Ocular rosaeea and more
`severe inflammatory rosaeea respond well to oral
`doxyeycline or minocycline, and in rare cases
`isotretinoin may be useful.
`
`SUMMARY
`
`The goal of acne treatment is to stop the formation
`of new cornedos, or pimples, and to reduce the
`severity of skin lesions. Several topical medica—
`tions are available that will control or reduce, if not
`
`

`

`:Iim'cal CORNERSTONE ' OFFICE DERMATOLOGY ' Vol 4 No I
`
`eliminate, all but the most severe acne. Oral therapy
`
`SUGGESTED READING
`
`should be prescribed for the most hard—to-tneat acne
`and topical steroids should not be used. Rosacea
`also responds well to topical therapy. The primary
`care physician should communicate clearly with the
`patient stressing that there are no “quick fixes" and
`acne and t'osaeea take time to respond to treatment.
`
`Plewig G. Kligman AM. Acne and Rosacea. 2nd
`ed. Berlin. Germany: Springer-Verlag; 1993.
`
`Webster GF. Inflammation in acne vulgaris. J Am
`Acad Dennatol. 1995;33:247—253.
`
`-, 1"
`ullk ‘ .
`.
`
`ADVISORY BOARD
`
`How do you initiate treatment with
`isotretinoin?
`
`Dialogue Box
`
`WEBSTER
`
`compare?
`
`WEBSTER
`
`.
`
`Although the recommended dose is 0.5 to 2.0
`mg/kg per day. that is not a prudent initial dose.
`I typically stan isotretinoin at 20 mg a day since
`there‘s always a risk of a flare when you start with
`a higher dose. By starting at a low dose. you
`minimize the flare. After the first month if the
`medication has been well tolerated, I generally
`increase the dose to a milligram per kilogram.
`
`ADVISORY BOARD
`
`Do you split the dose into 2 equal doses?
`
`WEBSTER
`
`It’s hard enough to get
`No. I don't split it.
`patients. especially adolescents. to take a medica—
`tion once a day.
`I tell them to take it once with
`food. This gives them high blood levels. and it’s
`actually better than twice a day without food so
`far as the half-life is concerned. The only reason
`
`why splitting the dose is listed as an option is
`because that‘s how it was used in the original
`studies.
`
`ADVISORY BOARD
`
`What is the impact of isotretinoin on the repro-
`
`ductive potential of male patients treated with
`this agent?
`
`Although isotretinoin is teratogenic in women,
`this is not the case in males.
`In fact, the only thing
`isotretinoin does to sperm is correct aberrant
`motility. Thus. it can potentially make men who
`are relatively infertile more fertile.
`
`ADVISORY BOARD
`
`Isn’t isotretinoinrn prokeloidal agent? Isn’t it
`more of a problem in black patients?
`
`WEBSTER
`We still don’t know whether that’s true. The cur-
`
`rent dogma is that isotretinoin is a prokeloidal agent
`in everybody. notjust blacks. Thus. you don’t want
`to perform a surgical procedure. particularly a derm-
`abrasion or a laser abrasion, while a patient is taking
`isotretinoin and maybe not for a while after the
`patient stops taking it. However. studies are lacking
`to say whether that's even true. We do know that
`isotrctinoin and all the oral retinoids predispose you
`to the development of pyogenic granulomas, and
`that is the main reason not to do surgery while a
`
`patient is taking isotretinoin. In addition. no one
`knows what the waiting time is before it‘s safe to
`
`perform a dcrmabrasion. Some dermatologists say
`a year because it takes that long for the sebaceous
`glands to come back, but no one really knows.
`
`ADVISORY BOARD
`
`How do the 3 main anticomedonal agents
`
`

`

`tII'IIt‘tnICORNERSTONE ' OFFICE DERMATOLOGY I Vol.4 Natl
`
`Dialogue Box
`
`limiting factor. And it is no longer necessary to
`titrate the concentration from 2.5% to 5% to as
`
`high as 10% to 20%. The important thing is to
`make sure that patients apply it everywhere they
`get a pimple and not just spot-treat.
`
`ADVISORY BOARD
`
`How do you use azelaic acid?
`
`WEBSTER
`
`Azelaic acid is a weird drug. Although it‘s weak
`on its own, if you add it to benzoyl peroxide it
`works as well as a drug such as Benzamycin®.
`Studies are going on now to determine whether
`a7elaie acid is doing anything or if the benzoyl per—
`oxide alone is as effective as Benzamycin® and the
`a7elaic acid is just riding along.
`I use it panieularly
`in black patients and medium-pigmented patients
`because it’s also a “melanocyte discourager" and
`makes the postinflammatory hyperpigmentation go
`away. If you talk to black patients and tease out
`what they hate most about acne, it’s the fact that
`they get postintlammatory pigmentation that out-
`lives the original acne lesion by many weeks.
`
`ADVISORY BOARD
`
`In patients with acne rosacea, how do you treat
`those patients with solely telangiectatic lesions?
`How do you treat patients with primarily pustu-
`lar lesions arising from sebaceous hyperplasia?
`
`WEBSTER
`
`When you average them out and survey demratol-
`ogists, most would say that adapalene is the weak-
`est comedolytic but the least irritating. tretinoin is
`in the middle, and tazarotene, although slightly
`more irritating. is probably most effective. Over a
`very narrow range, the degree of skin imitation
`induced is proportionate to their efficacy, but the
`resulting imitation is not necessarily treatment
`limiting. They are all good drugs.
`
`ADVISORY BOARD
`
`Why do benzoyl peroxides prevent drug
`resistance?
`
`WEBSTER
`
`Because they are antiseptics not antibiotics. Ben-
`zoyl peroxide is an oxidizing agent that gener~
`ates a lot of peroxide most bacteria are simply not
`capable of standing up to. By effectively reducing
`the total number of bacteria. you naturally have a
`lower probability of fostering a mutation that is
`resistant.
`In addition. even if you have resistance
`
`present. you’re not dealing with the selective force
`of l antibiotic that they can grow through.
`
`ADVISORY BOARD
`
`Does the old adage that you have to make the
`skin “red and dry” with benzoyl peroxide for
`it to be effective have any merit?
`
`as Noritate'” or MetroGel®.
`
`WEBSTER
`
`WEBSTER
`
`That rationale harkens back to the days when
`acne was treated with peels and benzoyl peroxide
`was used as a peeling agent. Studies have since
`demonstrated that the main mechanism of action
`
`is the killing ofP acne: and the weakest available
`benzoyl peroxide formulation is as effective as the
`strongest. As a result. concentration of the hen-
`zoyl peroxide should no longer be regarded as the
`
`Telangiectatic lesions are fairly resistant to any-
`thing other than laser treatment. Since no medica-
`tions will shrink telzmgiectascs. I turn the pulse
`dye laser on them to make them go away. For
`sebaceous hyperplasia. a variety of topical and
`systemic agents are available.
`I typically initiate
`treatment with a topical metronidazole agent such
`
`

`

`Does Norilate have FDA approval for the treat-
`ment of the erythcma associated with acne
`rosacea?
`
`WEBSTER
`
`Yes. but when you look at how the studies were
`done. erythcma alone was not differentiated from
`peri-lesional erythema. When the FDA was judg-
`ing the efficacy of Norilate against erythema, it
`was not againstjust blush and telangiectases but
`the redness that surrounded pustules.
`
`How does tetracycline work in acne rosacea?
`
`WEBSTER
`
`Tetracycline is a great drug for rosacea. Since P
`acne: plays no role in acne rosacea. lclracycline‘s
`efficacy stems more from its antineutrophil chemo-
`lactic and anti-inflammatory effects than its anti-
`bacterial action. This is why erythromycin is not
`as good as tetracycline—it's not as anti-inflamma-
`
`L‘IA'm'mlCORNERSTONI-Z I OFFICE DERMATOLOGY I V014 Nol
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`Dialogue Box
`
`ADVISORY BOARD
`
`ADVISORY BOARD
`
`tory as the tetracycline family.
`
`