fallclinical_march08

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Articles in this supplement are based

on selected presentations from the

2007 Fall Clinical Dermatology Confere n c e®

held October 18–21, 2007 in Las Vegas, NV.

skinskin& AGING

Supplement to the March 2008



S U P P L E M E N T T O S K I N & A G I N G • M A R C H 2 0 0 8 • 3

Acne vulgaris is one of the

most common diagnoses

e n c o u n t e red in cl inical

practice. Most advances relate to

i m p rovements in vehicle technolo-

gy and new data, especially on

combination therapy.

C O M B I N ATION TO P I C A L

T H E R A P Y

Topical retinoids are a vital component of both initial tre a t-

ment and maintenance therapy for acne vulgaris. They

exhibit the ability to reduce both non-inflammatory lesions

and inflammatory acne lesions. Benzoyl peroxide also

remains a foundation of acne treatment, exhibiting the abil-ity to markedly reduce P ropionibacterium acnes c o u n t s

and prevent emergence of P. acnes strains that are less

sensitive to antibiotics, such as erythromycin and tetracy-

cline. Benzoyl peroxide, including formulations that also

contain clindamycin, is well established for reducing inflam-

matory acne lesions but also for decreasing non-inflamma-

tory lesions by approximately 25% to 30% in clinical trials.

Multiple clinical trials have evaluated tretinoin (Retin-A

M i c ro, Tretin-X, Atral in), adapalene (Differin), and tazaro t e n e

( Tazorac), including initial pivotal monotherapy studies and

trials utilizing combination therapy with a benzoyl pero x i d e

(BPO)-containing formulation. The availability of newer vehi-cles that decrease the potential for and the intensity of initial

skin irritation observed with topical retinoid therapy ( “re t i n o i d

dermatitis”), such as tretinoin formulated in the micro s p h e re

gel (Retin-A Micro) and the aqueous-based gel (Atralin), has

allowed for effective combination topical therapy of acne vul-

garis from the outset. With these newer vehicles, more

patients are able to tolerate combination topical tre a t m e n t

with few or no signs of skin irritation.

B E N Z O Y L PEROXIDE/CLINDAMYCIN +

TO P I C A L RETINOID T H E R A P Y

Clinical studies have evaluated BPO-clindamycin gel (Duac)

used in combination with either tazarotene cream 0.1% (Ta z o r a c ) ,

t retinoin micro s p h e re gel 0.04% or 0.1% (Retin-A Micro), or ada-

palene gel 0.1% (Differin). The BPO-clindamycin gel and the top-

ical retinoid were applied in the morning and at bedtime, re s p e c-

t i v e l y, in all of the studies. The combination topical approach of a

retinoid used along with BPO-clindamycin from the outset of ther-

apy exhibited inflammatory and non-inflammatory lesion re d u c-

tions after 12 weeks of at least 60% and 55%, re s p e c t i v e l y, with

all 3 retinoids (F i g u res 1–4). In one of the trials, the study arm

using both BPO-clindamycin gel (Duac) and tazarotene 0.1%

c ream (Tazorac) demonstrated a marked reduction in non-inflam-

matory lesions at Week 4 (34%) and Week 8 (64%) (F i g u re 3) .

Tolerability results were very favorable in all 3 trials. A case re p o r t

series of BPO micro s p h e re cream (NeoBenz Micro) applied oncedaily in the morning used in combination with tretinoin micro s-

p h e re gel 0.04% (Retin-A Micro) once daily at night also proved to

exhibit effective results with no reports of skin irritation.

PROPER SKIN CARE IN ACNE T H E R A P Y

The use of appropriate skin care is vital in the management

of acne vulgaris, allowing for preservation of epidermal barrier

integrity and function. The use of a gentle facial cleanser and

James Q. Del Rosso,

D.O., F.A.O.C.D.

BY JAMES Q. DEL ROSSO, D.O., F.A.O.C.D.DERMATOLOGY RESIDENCY DIRECTOR

VALLEY HOSPITAL MEDICAL CENTER

LAS VEGAS, NV

FALL CLINICALDERMATOLOGY 2007AN UPDATE ON ADVANCES IN ACNE AND EXCERPTS FROMWHAT’S NEW IN THE MEDICINE CABINET

FA L L C L I N I C A L D E R M ATO L O G Y CO NF ER EN CE PR OC EE DI NG S

NEWER VEHICLES T H AT D E C R E A S E

THE POTENTIAL FOR AND THE

I N T E N S I T Y OF INITIAL SKIN IRRITAT I O N

O B S E RVED WITH TO P I C A L R E T I N O I D

T H E R A P Y H AVE ALLOWED FOR

EFFECTIVE COMBINATION TO P I C A L

T H E R A P Y OF ACNE VULGARIS.

ACNE UPDATE



well-formulated moisturizer both reduces the potential for skin

irritation associated with topical medications and enhances the

ability of acne medications to reduce lesions. A pre p a c k a g e d

kit is available that contains tretinoin cream, a gentle cleanser

and a moisturizer (Tretin-X), thus providing an additional “con-

venience value.” A recent study evaluating the use of

t a z a rotene 0.1% cream (Tazorac) and a ceramide-based mois-

turizer cream (CeraVe Cream) in subjects with acne vulgaris

demonstrated that application of the moisturizer first did not

i n t e r f e re with therapeutic results and mitigated signs andsymptoms of skin irritation.

NEWER TO P I C A L RETINOID FORMULAT I O N S

Newer topical retinoid formulations that have emerged add

to the dermatology armamentarium. Adapalene gel 0.3%

( D i fferin 0.3%) once daily has been shown to produce two-

t h i rds of its therapeutic effect within the first month of tre a t-

ment. A water-based gel containing tretinoin 0.05% (Atralin)

applied once daily proved to be comparable to, but not non-

inferior to, tretinoin micro s p h e re gel 0.1% (Retin-A Micro) based

on data from a 12-week controlled study; however, tolerability

was superior with the aqueous-based gel.

A combination aqueous polymer gel containing clin-

damycin phosphate 1.2% and tretinoin 0.025% (Ziana)

includes tretinoin in both solubilized and crystalline forms. The

crystalline form of tretinoin allows for slow release of active

drug with very low skin irritation, and particle size is tightly

controlled, thus providing optimal penetration. The superiorefficacy of the combination clindamycin/tretinoin gel applied

once daily as compared to individual active components was

established in large, Phase III trials in subjects with mild, mod-

erate, and severe acne vulgaris (Figure 5).

NEWER BENZOYL PEROXIDE FORMULAT I O N S

Newer formulations of BPO appear to offer the advantages

of reduced skin irritation without loss of efficacy and potential-

4 • M A R C H 2 0 0 8 • S U P P L E M E N T T O S K I N & A G I N G




ly superior efficacy in some cases, as compared to some older

formulations (F i g u re 6). A “triple moisturizer- i n g redient formula-

tion” (Benziq), available as a wash and “leave on” gel, was

shown to be less irritating than some other comparator BPO

p roducts in a cumulative irritancy study. The micro s p h e re

c ream formulation of BPO 5.5% (NeoBenz Micro) has demon-

strated efficacy in clinical studies with a very favorable tolera-

bility profile; one study demonstrated superior efficacy with the

t retinoin micro s p h e re cream (NeoBenz Micro) as compared to

benzoyl peroxide gel 6% (Triaz) in patients with acne vulgaris.

A “direct from the doctor” 3-part acne treatment system

(Clenziderm MD, Normal to Oily Skin) utilizing a salicylic acid

2%-containing cleanser and “pore gel” followed by a 5% gel

containing solubilized BPO has been evaluated in several trials.

Unlike conventional BPO formulations, the solubilized BPO inthe 3-part proprietary system is micronized such that individual

BPO particles are small enough to penetrate into the follicular

orifice where P. acnes resides. This 3-part acne treatment sys-

tem has demonstrated both reduction in P. acnes and eff i c a c y

comparable to benzoyl peroxide/clindamycin gel (Benzaclin) in

p reliminary trials along with high patient pre f e rence ratings.

Another 3-part acne treatment system, available from the

same manufacture r, contains solubilized BPO 5% lotion com-

bined with a gentle cleanser and moisturizer (Clenziderm MD,

Normal to Dry Skin) and does not contain the components with

salicylic acid 2%.

O R A L CONTRACEPTIVES IN ACNE T H E R A P Y

The majority of post-teenage females with acne exhibit

normal serum androgen levels. Acne appears to occur sec-

ondary to increased local androgen production within seba-

ceous glands. Many adult-onset or adult-persistent cases of

acne vulgaris in females present with a preponderance of

inflammatory lesions involving the lower cheeks, jawline,

chin and lateral neck.

The only progestin available in an oral contraceptive (OC)

formulation that exhibits antiandrogen activity is dro s p e r i n o n e

found in a formulation that also contains 20 mcg of ethinyl

estradiol (YAZ). This formulation is approved for moderate acne

and is comprised of 24 days of active therapy and 4 hormone-

f ree days, resulting in a short menstrual cycle. In a placebo-

c o n t rolled, randomized, double-blind, 6-cycle clinical study,

451 females received the active OC formulation and 442

received placebo. After the first cycle, subjects receiving active

OC treatment demonstrated a markedly greater reduction in

total acne lesions, which continued to pro g ress throughout the

sixth cycle (study endpoint).

When using OCs to treat females with acne vulgaris, side

effects may be decreased by using formulations that contain

lower doses of the estrogenic component (ethinyl estradiol).

In addition to reduction in acne lesions, other potential bene-fits of OC use include regulation of menstrual cycle, reduction

in perimenstrual symptoms, such as cramping, decrease in

ovarian cyst formation, reduction in bone demineralization,

and decrease in risk of ovarian and colorectal cancer.

Potential side effects of OC use include thromboembolism

and cerebral vascular accident. It has been recommended

that clinicians not prescribe OCs to women who smoke due

to an increased risk of vascular-related complications.



ACNE APPEARS TO OCCUR

SECONDARY TO INCREASED LOCAL

ANDROGEN PRODUCTION WITHIN

SEBACEOUS GLANDS.



O R A L ANTIBIOTICS IN ACNE T H E R A P Y

Dermatologists have been prescribing oral antibiotics,

such as tetracycline, doxycycline and minocycline, for acne

vulgaris since the 1950s, 1960s and 1970s, re s p e c t i v e l y,

based on clinical experience and a scattered collection of

small clinical studies. However, extended-release minocy-

cline (Solodyn) is the only oral antibiotic that is approved by

the U.S. Food and Drug Administration (FDA) based on

large-scale, Phase III studies demonstrating efficacy and

s a f e t y. The extended-release formulation of minocycline

p roduces a slower time to peak plasma level (Cmax) and a

d e c rease in total cumulative exposure to minocycline asc o m p a red to immediate- release minocycline formulations.

Results from Phase II and Phase III trials substantiate ther-

apeutic equivalence for acne vulgaris with extended-

release minocycline when dosed at 1 mg/kg/day as com-

p a red to 2 mg/kg/day and 3 mg/kg/day. Importantly, a

marked ly lower incidence of acute vestibular side eff e c t s

(ie, dizziness) comparable to placebo was seen at 1

mg/kg/day as compared to higher doses.

An enteric-coated tablet of doxycycline (Doryx) appears to

p rovide reduced gastrointestinal (GI) upset as compared to

i m m e d i a t e - release doxycycline formulations. However, enteric

coating is not synonymous with extended-release and serves

to delay initial gastric dissolution in an attempt to reduce GI

upset. Enteric coating may allow for once-daily administration

in some patients when using 150 mg to 200 mg of doxycycline

d a i l y. With the exception of anti-inflammatory dose doxycycline

a d m i n i s t e red once daily, ie, doxycycline 40-mg delayed-re l e a s e

capsule (Oracea), all other formulations of doxycycline pro d u c e

antibiotic activity. Anti-inflammatory dose doxycycline is FDA-

a p p roved for treatment of rosacea. There is no scientific evi-

dence that pill splitting of any tablet formulation of doxycyclinep roduces anti-inflammatory activity without an antibiotic eff e c t .

W H AT’S NEW IN THE MEDICINE CABINET

T R E ATMENTS FOR ROSACEA

The only FDA-approved oral therapy for rosacea is anti-

inflammatory dose doxycycline (Oracea), administered as a

patented doxycycline 40-mg delayed-release capsule once

d a i l y. The mechanism of anti-inflammatory dose doxycycline

appears to relate at least partially to downregulation of the activ-

ity of several matrix metalloprotease enzymes (MMPs). Anti-

inflammatory dose doxycycline offers advantages over conven-tional oral antibiotic therapy. These include efficacy with a favor-

able safety profile, presence of long-term 9-month safety data

included in approved product labeling, and lack of antibiotic

activity as determined by long-term microbiologic studies evalu-

ating oral, skin, gastrointestinal and vaginal flora. The absence

of antibiotic activity with anti-inflammatory dose doxycycline is

supported by the absence of vaginal candidiasis in female sub-

jects who were actively treated in the pivotal Phase III studies.


THERE IS NO SCIENTIFIC

EVIDENCE THAT PILL SPLITTING

OF ANY TABLET FORMULATION OFDOXYCYCLINE PRODUCES

ANTI-INFLAMMATORY ACTIVITY

WITHOUT AN ANTIBIOTIC EFFECT.




Unlike anti-inflammatory dose doxycycline, doxycycline

100 mg daily administered over a 2-week period has been

shown to select for multiple resistant organisms within 7 days,

with more than 32.2% of organisms obtained from nasopha-

ryngeal cultures demonstrating resistance to doxycycline as

compared to 2.2% at baseline. Doxycycline 50 mg once daily

achieves serum levels that exceed the minimum inhibitory

concentration (MIC) of several bacteria for 2 to 4 hours.

A study evaluating the combination of metronidazole gel 1%

( M e t roGel 1%) and anti-inflammatory dose doxycycline

(Oracea), both used once daily, confirmed that the combination

regimen produced superior therapeutic benefit as compared to

topical metronidazole alone in patients with inflammatory

rosacea. After 4 weeks, the combination regimen pro d u c e d

essentially the same reduction in inflammatory lesions that was

achieved with metronidazole gel 1% over 12 weeks (F i g u re 7) .

A recent trial demonstrated that azelaic acid gel 15%

(Finacea) once daily is therapeutically equivalent to twice-

daily application in subjects with inflammatory ro s a c e a

(F i g u re 8). Study endpoints utilized quantitative, qualitative,

and static assessments, including lesion count evaluations

and global assessments. Once-daily use of azelaic acid gel

15% is more likely to be associated with optimal compli-

ance and offers a cost benefit over time as compared to

twice-daily application.

T R O L A M I N E - C O N TAINING TO P I C A L E M U L S I O N

Trolamine-containing topical emulsion (Biafine) is an oil-in-

water formulation that has been used for more than 3 decadesin both the United States and Europe. The mechanism of

action of trolamine-containing topical emulsion appears to be

p romotion of an increase in the number of macro p h a g e s

recruited to the injury site, thereby reducing the time needed for

healing. Macrophages promote wound healing and serve a

central role in directing the course and pro g ression of the

wound-healing process. Therapeutic applications for tro l a m i n e -

containing topical emulsion include full-thickness wounds,

superficial wounds, including those that are postoperative, der-

mal ulcers, radiation dermatitis, minor abrasions, actinic ker-

atosis treatment sites after cryotherapy, and wounds that

re q u i re second-intention healing after dermatologic surgery. The use of trolamine-containing topical emulsion for the

t reatment of radiation dermatitis has made it possible to

reduce overall treatment time of chemotherapy and radiother-

apy because the modalities could be administered simultane-

ously rather than sequentially. Additionally, tro l a m i n e - c o n t a i n-

ing topical emulsion differs from topical neomycin and baci-

tracin because the latter 2 agents are well recognized as com-

mon causes of contact allergy.

References

1. Del Rosso JQ. Recently approved systemic therapies for acne vulgaris

and rosacea. Cutis . 2007;80(2):113–120.

2. Plott RT, Wortzman MS. Key bioavailability features of a new extended-

release formulation of minocycline hydrochloride tablets. Cutis . 2006;78(4Suppl):6–10.

3. Fleischer AB Jr, Dinehart S, Stough D, et al. Safety and efficacy of a newe x t e n d e d - releas e formulation of minocyc line. C u t i s . 2006;78(4

Suppl):21–31.

4. Del Rosso JQ. Scientific panel on antibiotic use in dermatology. Submitted

for publication 2008.

5. Del Rosso JQ, Webster GF, Jackson M, et al. Two randomized phase IIIclinical trials evaluating anti-inflammatory dose doxycycline (40-mg doxycy-

cline, USP capsules) administered once daily for treatment of rosacea. J AmAcad Dermatol . 2007;56(5):791–802.

6. Webster G, Del Rosso JQ. Anti-inflammatory activity of tetracyclines.Dermatol Clin. 2007;25(2):133–135.

7. Walker C, Webster GF, Del Rosso JQ. Effect of doxycycline 100 mg daily

on emergence of antibiotic resistance. Presented at the Fall ClinicalDermatology Conference in Las Vegas, NV, October 18–21, 2007.

8. Fowler JF Jr. Combined effect of anti-inflammatory dose doxycycline (40-

mg doxycycline, USP monohydrate cont ro l l e d - release capsules) andmetronidazole topical gel 1% in treatment of rosacea. J Drugs Dermatol .

2007;6(6):641–645.

9. Fleischer AB, Thiboutot D, Del Rosso JQ. Comparison of azelaic acid gel15% once daily versus twice daily in the treatment of rosacea. Presented at

the World Congress of Dermatology in Buenos Aires, Argentina, October1–5, 2007.

10. Data on file. Allergan Inc., Irvine, CA, 2008.

11. Del Rosso JQ, Tanghetti E. The clinical impact of vehicle technologyusing a patented formulation of benzoyl peroxide 5%/clindamycin 1% gel:

comparative assessments of skin tolerability and evaluation of combinationuse with a topical retinoid. J Drugs Dermatol . 2006;5(2):160–164.

12. Del Rosso JQ. Study results of benzoyl peroxide 5%/clindamycin 1%

gel, adapalene 0.1% gel, and use in combination for acne vulgaris. J Drugs Dermatol . 2007;6(6):616–622.

13. Tanghetti E, Abramovits W, Solomon B, et al. Tazarotene versustazarotene plus clindamycin/benzoyl peroxide in the treatment of acne vul-garis: a multicenter, double-blind, randomized, parallel-group trial. J Drugs

Dermatol . 2006;5(3):256–261.

14. Bikowski JB, Del Rosso JQ. Results of a case report series using

tretinoin microsphere cream alone and in combination regimens for acne vul-garis. Submitted for publication 2008.

15. Del Rosso JQ, Bikowski JB. Trolamine-containing topical emulsion: clin-

ical applications in dermatology. Cutis . In press.

16. Broughton G 2nd, Janis JE, Attinger CE. The basic science of woundhealing. Plast Reconstr Surg . 2006;117(7 Suppl):12S–34S.






There have been few, if

any, new systemic or top-

ical medications devel-

oped in the last few years for the

treatment of rosacea, so often-

times, advancement in therapy

relies upon the correct diagnosis.

The right medicine will not work

with the wrong diagnosis. For

every individual who pre s e n t s

with a red, scaly face, the derma-

tologist will consider the differential diagnoses: rosacea, seb-

orrheic dermatitis, irritant contact dermatitis, allergic contact

dermatitis, etc. Is it really rosacea? Are there other things that

can look like rosacea?

D I F F E R E N T I A L DIAGNOSES AND UNUSUAL

FACES OF ROSACEA

D e m o d ex d e r m a t i t i s . When patients present with red, scaly

faces, the first consideration is whether there is an “infectious”

component or an infestation that can be cured or suppre s s e d

for a prolonged period of time. Cases of D e m o d e x d e r m a t i t i s

can be treated with permethrin (Elimite) or crotamiton (Eurax)

twice daily, morning and night, for 2 to 4 weeks.

Case 1. A patient had been treated for almost 2 years for

rosacea and then seborrheic dermatitis without improvement

(Figure 1). A potassium hydroxide (KOH) preparation revealed

Demodex . Because no other treatment had been effective,the patient was started on Elimite twice daily, and within 2

weeks, his face cleared. The red, scaly rash over his fore-

head, nose and malar eminence disappeared. The patient

remained clear at 1-year follow-up.

Rosacea, seborrheic dermatitis and D e m o d e x d e r m a t i t i s

can exist separately or together. Oftentimes, the red scal-

ing is not seborrheic dermatitis with rosacea or seborrheic

dermatitis alone. Rather, it may be D e m o d e x d e r m a t i t i s .

Patients in whom the diagnosis of rosacea is suspected

should have KOH preparations performed on scrapings of

the scales from their faces and empirical treatment with

either Elimite or Eurax twice daily, morning and night, for 2

weeks. Individuals who are not improving with anti- ro s a c e a

therapy or anti-seborrheic dermatitis therapy who still have

red, scaly faces should receive one of these topicals twice

daily for 2 to 4 weeks.

Steroid use/abuse/misuse dermatitis. Another unusual

p resentation that may resemble rosacea is stero i d

use/abuse/misuse dermatitis. Any cortisone molecule used

frequently over a long period of time in a susceptible individ-

ual can produce steroid use/abuse/misuse dermatitis.

Case 2. A 26-year-old woman presented with an

intensely pruritic, erythematous, scaly, papular eruption of 6

months’ duration on her face (F i g u re 2). For that period of time, she had been applying a topical corticosteroid to her

face 4 times daily. The steroid responsible for this was

0.5% hydrocortisone cream.

Plaque ro s a c e a . The usual presentation for rosacea is erythe-

ma, papules and pustules on the central third of the face.

H o w e v e r, there is a presentation called plaque rosacea in which

erythema, edema, papules and pustules appear only in one iso-

lated area, ie, on one cheek (F i g u re 3). These patients re s p o n d

to rosacea therapy, especially systemic therapies.

Joseph Bikowski, M.D.

IS IT REALLY ROSACEA?

A DISCUSSION OF DIFFERENTIAL DIAGNOSES, TREATMENTS

AND ADVANCES IN RESEARCH


BY JOSEPH BIKOWSKI, M.D.BIKOWSKI SKIN CARE CENTER

SEWICKLEY, PA

PATIENTS IN WHOM THE DIAGNOSIS

OF ROSACEA IS SUSPECTED SHOULD

HAVE KOH PREPARATIONS

PERFORMED ON SCRAPINGS OF THE

SCALES FROM THEIR FACES.



U S U A L THERAPIES FOR ROSACEA

van Zuuren et al1 conducted a literature review of 71 ran-

domized, controlled studies of rosacea therapy. Of the 71

studies, 29 met their inclusion criteria, but the quality in gen-

eral of these studies was not considered very good. The

conclusions were that topical metronidazole and azelaic acid

a re effective therapies for rosacea. There was some evi-

dence that oral metronidazole and tetracycline including

doxycycline and minocycline are effective, but the take-away

message was that there is a great need for randomized, con-t rolled trials examining the efficacy of present medications for

the treatment of ro s a c e a .

Del Rosso et al2 conducted two such randomized, Phase

III clinical trials evaluating the anti-inflammatory doxycycline

40 mg a day administered once daily for the treatment of

rosacea. They concluded that once-daily anti-inflammatory

dose doxycycline appears to be effective and safe for the

t reatment of ro s a c e a .

U N U S U A L T R E ATMENTS FOR ROSACEA

Skin care. The skin of the rosacea patient can be either oily

or dry. Certainly, it can be extremely sensitive in some cases.

There can be altered cutaneous vascular reactivity and, most

importantly, skin barrier dysfunction, which is defined as

increased transepidermal water loss, increased susceptibility

to irritants, allergens and pathogens, and increased skin

inflammation through cytokine-mediated lipogenesis.

Skin barrier dysfunction exists in most inflammatory dis-

eases, including atopic dermatitis, psoriasis, acne and aged,actinicly damaged skin. The stratum corneum is a “bricks” and

“mortar” structure. Corneocytes are the bricks, and sitting

between the corneocytes is the mortar, the lipid matrix, which

has a certain constitution that needs to be re s t o red. Ceramides

a re most important, constituting about 40% to 50% of the lipid

matrix. In addition to the ceramides, the lipid matrix contains

f ree sterols and free fatty acid. There are also lipid bilayers,

which become a moisture barrier for the stratum corn e u m .



FIGURE 1. DEMODEX DERMATITIS: AT BASELINE (LEFT) AND AFTER 2 WEEKS OF TREATMENT WITH PER-

METHRIN TWICE DAILY (RIGHT).

BASELINE AFTER 2 WEEKS



A d d i t i o n a l l y, inside the corneocytes is natural moisturizing fac-

t o r. All of these can be disrupted in inflammatory diseases, so

restoring them as part of skin care and treatment for ro s a c e a

and other inflammatory diseases is most important.

Products that can restore the skin barrier are available over

the counter and soon by prescription. CeraVe is available over

the counter as a cleanser and a moisturizer. Another over-the-

counter product is Triceram from Osmotics, and Elizabeth

Arden also has a line of products available over the counter.

Patients being treated for inflammatory skin disease, espe-

cially rosacea, should be encouraged to purchase one of

these products as a cleanser and a moisturizer.

I s o t re t i n o i n . I s o t retinoin is effective in the treatment of the

facial edema that can be associated with acne, and it also is an

e ffective treatment for rosacea. Isotretinoin 30 mg twice daily

for the treatment of rosacea is an off-label indication, but it is

something to consider.

A s p i r i n . While papules and pustules are not much of a chal-lenge, erythema can be. There is an increased incidence of

rosacea patients with migraine headaches. Both rosacea and

migraines are vascular dilatation phenomena. The re p e a t e d

flushing associated with rosacea leaves one with persistent ery-

thema. Neurologists recommend aspirin 81 mg long acting as

p rophylaxis against migraine headaches. It also works for

rosacea flushing and blushing. If patients are asked to keep

track of their flushing and blushing episodes with a calendar

diary for 30 days after starting on 81 mg of aspirin daily it

becomes evident that the episodes of flushing decrease in

s e v e r i t y, intensity and rates of occurrence.

Wa t e r-based emulsion or nonsteroidal cre a m . O t h e roptions for treating the erythema of rosacea are water- b a s e d

emulsions or nonsteroidal creams. In a patient who has per-

sistent erythema in whom D e m o d e x dermatitis has been ruled

out, use of Mimyx or Atopiclair may be effective (F i g u re 4).

A D VANCES IN BASIC RESEARCH

Yamasaki and colleagues3 at the University of

C a l i f o rnia, San Diego, have been studying cathe licidin

1 0 • M A R C H 2 0 0 8 • S U P P L E M E N T T O S K I N & A G I N G


FIGURE 2. STEROID USE/ABUSE/MISUSE DER-

MATITIS: A 26-YEAR-OLD WOMAN WITH

A 6-MONTH HISTORY OF AN ERYTHE-

MATOUS, PAPULAR, SCALY, INTENSELY

PRURITIC FACIAL ERUPTION.

FIGURE 3. PLAQUE ROSACEA: A 48-YEAR-OLD

MAN WITH A 2-YEAR HISTORY OF AN

EDEMATOUS, ERYTHEMATOUS PAPULE

AND PUSTULE STUDDED LESION OF

THE LEFT CHEEK.

THERE IS AN INCREASED INCIDENCE

OF ROSACEA PATIENTS WITH

MIGRAINE HEADACHES. BOTH

ROSACEA AND MIGRAINES ARE

VASCULAR DILATATION PHENOMENA.



and stratum corneum tryptic enzymes, which lead to

abnormal peptides and the signs and symptoms of

rosacea. They discovered increased levels of cathelicidin

and diff e rent cathelicidins in patients who have ro s a c e a

versus those who do not have rosacea, and these pep-

tides can lead to inflammation, which can be blocked by

the use of antibiotics. Further study is warranted to

determine how decreasing cathelicidin will advance

rosacea therapy.

C O N C L U S I O N

Few new medications have been developed for the tre a t-

ment of rosacea in recent years; however, even the newest

rosacea treatment will not be effective if the patient does not

have rosacea. In treating cases of suspected rosacea, it is

important for the dermatologist to consider the diff e re n t i a l

diagnoses, such as seborrheic dermatitis and irritant/allergic

contact dermatitis, and also to be aware of unusual pre s e n t a-

tions of rosacea, such as plaque rosacea. Basic skin care

remains essential in the treatment of patients with ro s a c e a ,

and new products that have become available over the count-

er offer patients a wider variety from which to choose. Finally,

further re s e a rch on the role of cathelicidin in rosacea may pro-

vide dermatologists new treatment options in the future.

References

1. van Zuuren EJ, Gupta AK, Gover MD, Graber M, Hollis S. Systematicreview of rosacea treatments. J Am Acad Dermatol . 2007;56(1):107–115.

2. Del Rosso JQ, Webster GF, Jackson M, et al. Two randomized phase III

clinical trials evaluating anti-inflammatory dose doxycycline (40-mg doxycy-cline, USP capsules) administered once daily for treatment of rosacea. J Am

Acad Dermatol . 2007;56(5):791–802.

3. Yamasaki K, Di Nardo A, Bardan A, et al. Increased serine protease activ-

ity and cathelicidin promotes skin inflammation in rosacea. Nat Med .2007;13(8):975–980.

S U P P L E M E N T T O S K I N & A G I N G • M A R C H 2 0 0 8 • 1 1


FIGURE 4. ERYTHEMA OF ROSACEA: A 41-YEAR-OLD WOMAN WITH PERSISTENT ERYTHEMA OF

ROSACEA BASELINE AND AFTER 4 WEEKS OF MIMYX TWICE DAILY.

BASELINE AFTER 4 WEEKS

A NEW AREA OF RESEARCH FOR

ROSACEA THAT APPEARS PROMISING

IS DETERMINING THE ROLE OF

CATHELICIDINS AND TRYPTIC

ENZYMES AND THEIR POSSIBLE

ASSOCIATIONS WITH ROSACEA.



While some dermatolo-

gists have been pre-

scribing oral contra-

ceptives for the treatment of acne

for many years with much suc-

cess, others are resistant. The

goal of this article is to assure the

safe, effective and efficient pre-

scription of oral contraceptives for

acne patients, which will result in

i m p rovements in patients’ acne

and their overall quality of life.

Acne is a complex multifactorial disord e r. Since there are

4 diff e rent causes in the pathogenetic process, combination

t reatments that target the multiple pathogenetic factors will

o ffer the greatest improvement in the shortest amount of

time. Oral contraceptives can be added to the armamentar-ium as another option for treatment.

The 4 causes of acne are follicular epidermal hyperpro l i f e r a-

tion, excess sebum, P ropionibacterium acnes and inflamma-

tion. During follicular epidermal hyperproliferation, plugging

causes the development of comedones and micro c o m e d o n e s .

For excess sebum, hormonal therapy, whether it is spiro n o l a c-

tone, flutamide or oral contraceptives, creates an antiandro g e n

e ffect that has most of its impact on the sebaceous gland.

While probably not the first event in the pathogenetic pro c e s s ,

P ropionibacterium acnes certainly is a cause. Also, whether or

not inflammation is the first event in the process or it is sec-

ondary to P. acne s is a difficult question to answer.Oral contraceptives are not monotherapy for acne; rather,

they fall into the mix of topical retinoids, benzoyl peroxides,

and antibiotics. The type of oral contraceptive prescribed for

acne is a combination of ethinyl estradiol and a progestin.

Ethinyl estradiol varies in dose from pill to pill from 20 micro-

grams to 50 micrograms in a pill. The amount of ethinyl estra-

diol is important, because many of the risk factors associated

with birth control pills are associated with higher doses of

ethinyl estradiol. The progestins in combination birth control

pills vary widely but may include norethindrone acetate, lev-

onorgestrel, desogestrel, norgestimate, and drospirenone

among others. Drospirenone is the only progestin available in

the United States that is antiandrogenic alone. Some other

progestins can be proandrogenic.

Oral contraceptives are antiandrogenic because ethinyl

estradiol in combination birth control pills increases sex hor-

mone binding globulin. Sex hormone binding globulin acts as

a sponge — it soaks up free testosterone and decreases the

amount that is free and circulating and capable of having its

impact at the sebaceous gland, for example. Also, there is a

negative feedback to the hypothalamus and pituitary, which

results in decreased production and release of gonadotropin

releasing hormone, luteinizing hormone and follicle stimulating

hormone. This then results in decreased ovarian production

of hormone. Also, because ovulation is blocked, the ovaryproduces less androgen.

The novel progestin, dro s p i renone, is equiva lent to about

25 mg of spironolactone when it is in a 3 mg dose, which

is available in 2 birth control pills that are on the market now

in the United States. Dro s p i renone has antimineralocorti-

coid properties as well.


Julie C. Harper, M.D.

TREATING ACNE WITH ORALCONTRACEPTIVESA GUIDE FOR SAFE, EFFECTIVE AND EFFICIENT PRESCRIBING


BY JULIE C. HARPER, M.D.UNIVERSITY OF ALABAMA – BIRMINGHAM

BIRMINGHAM, AL

Attendees focus on new clinical information.



WHICH ORAL CONTRACEPTIVE

WORKS IN ACNE?

It is likely that many oral contraceptives have some impact in

acne. The dermatologist should choose one or two pills with

which he or she feels comfortable and use those. The U.S.

Food and Drug Administration (FDA) approved 3 oral contra-

ceptives to treat acne: Estrostep, Ortho Tri-Cyclen and YA Z ,

which is the newcomer. YAZ was FDA approved for acne in

2007. A Cochrane meta-analysis evaluated 21 studies using

oral contraceptive pills in the management of acne. The num-

ber one conclusion is it is difficult to compare trials because

investigators in acne studies do not always use the same stan-d a rd to measure whether or not acne is improving. The only

real conclusion the authors could draw was that combination

oral contraceptive pills that contained either cypro t e ro n e

acetate or chlormadinone acetate — both of which are not

available in the United States — were more effective than oral

contraceptive pills that contained levonorgestrel.

One study compared the effect of Yasmin to Diane-35 on

cases of mild to moderate acne. Yasmin has dro s p i renone (3

mg), while Diane-35 has cypro t e rone acetate (2 mg), which

also is antiandrogenic. In the head-to-head comparison, 128

people were included for 9 cycles of treatment. In both

g roups, the lesion counts were reduced by about 60% and thesex hormone binding globulin increased 3-fold in both groups.

Yasmin also was compared head to head with Ortho Tr i -

Cyclen. The study enrolled more than 500 women in each gro u p

for 6 months of treatment. Yasmin was superior in reduction of

total lesion counts and investigator’s assessment, but in re d u c-

tion of inflammatory lesions, the two were fairly equivalent.

The newest oral contraceptive approved for the man-

agement of acne is dro s p i renone 3 mg and ethinyl estradi-

ol 20 micrograms (YAZ). In one study, 431 people were

e n rolled and received either YAZ or placebo. There was

about a 50% mean percent change in inflammatory lesions

by the end of the sixth month of treatment. Since this was

m o n o t h e r a p y, 50% reduct ion is an impressive change.

ORAL CONTRACEPTIVE RISKS

One reason dermatologists may not prescribe oral contra-

ceptives for their acne patients is the risks associated with

birth control pills. These risks include venous thromboem-

bolism, stroke, myocardial infarction and breast cancer.

Venous thromboembolism. The risk of venous throm-boembolism is tripled in current users of oral contraceptives.

It is increased to 4 to 18 events per 10,000 woman-years.

The risk increases with higher doses of ethinyl estradiol. Also,

the mortality rate doubles in women aged 35 to 45.

Stroke. There is a 2.5x increase in ischemic stroke in

women age 20 to 24 who use birth control pills. Again, the

risk is directly proportional to the ethinyl estradiol dose.

Choose pills that have a lower dose of ethinyl estradiol. The

risk increases with age. It also increases when other risk fac-

tors, such as cigarette smoking, hypertension and migraine

headaches, are present.

Myocardial infarction. Eighty percent of myocardial infarc-tions that occur in women who are on birth control pills occur

in women who also smoke cigarettes, with the remainder

occurring in oral contraceptive users with other risk factors,

such as hypertension or diabetes.

Breast cancer. A large World Health Organization meta-

analysis looked at more than 53,000 women with breast can-

cer and more than 100,000 controls. The relative risk of

breast cancer was 1.24 in current users of birth control pills

S U P P L E M E N T T O S K I N & A G I N G • M A R C H 2 0 0 8 • 1 3


Attendees learning the latest in the field.



and the relative risk of cancer that had spread versus

remained localized was 0.88. However, those risks are rare.

ORAL CONTRACEPTIVE BENEFITS

There are several protective benefits of birth control pills.

These benefits include protection against ovarian cancer,

endometrial cancer, pelvic inflammatory disease, uterine

leiomyomas, and ovarian cysts and regulation of the men-

strual cycle. There is a 40% to 80% overall decreased risk of

ovarian cancer in women who take birth control pills.

Protection begins after one year of use, increases by 10% to

12% annually, and persists for another 15 to 20 years after

the pill is discontinued. Similarly with endometrial cancer,

there is up to a 50% decreased risk of endometrial cancer in

women who take birth control pills. Again, protection begins

after one year, increases with duration of use, and persists for

up to 15 years after discontinuation of the medication.

ORAL CONTRACEPTIVE SIDE EFFECTS

Side effects reported with oral contraceptive use include

irregular bleeding, nausea, weight gain, mood changes and

breast tenderness. No clinical trials confirm that weight gain

is a problem with birth control pills. The thought is the ethinyl

estradiol causes water retention and associated weight gain.

Drospirenone, which has some antimineralocorticoid proper-

ties, also has a diuretic effect. Using drospirenone may offset

water retention and weight gain. Irregular bleeding is most

common in the first 3 months of treatment. Spotting is normal

during the first 3 months and does not require stopping treat-

ment or changing the pill. After the third month, it may be

necessary to increase the ethinyl estradiol dose and prescribea different pill. Irregular bleeding is one side effect that wors-

ens with lower ethinyl estradiol doses. Most other side effects

improve with lower ethinyl estradiol doses.

PRESCRIBING ORAL CONTRACEPTIVES

FOR ACNE

Prior to prescribing oral contraceptives for acne patients,

performing a pelvic exam is not necessary; however, taking a

history is necessary. Much of the pertinent information already

will be readily available in the patient’s chart, but it may be

necessary to spend a few extra moments talking with patients

about contraindications. Contraindications include pregnan-

cy; current breast cancer; breast feeding; age over 35 and

heavy smoker (more than 15 cigarettes a day); hypertension;

diabetes with nephropathy, retinopathy, neuropathy, and vas-

cular disease; deep vein thrombosis, history or current; histo-

ry of heart disease; history of stroke; and migraine headaches

with focal neurological symptoms at any age or without neu-

rological symptoms in patients > 35 years of age.

When prescribing oral contraceptives, give patients re a s o n-

able expectations. Improvement in acne is not expected until

the patient has been taking the oral contraceptive for 3 months

or longer. Consider combination therapy early in the tre a t m e n t

of acne. Many topical and systemic acne treatments will have

a positive impact on acne as early as 4 to 8 weeks. Discuss

potential side effects, namely irregular bleeding, and assure the

patient that it is not a sign of anything gone wrong if she spots

during the first 3 months of treatment.

There are several options for starting a birth control pill. One

is the Sunday of the next menstrual period. The next is the

first day of the next menstrual period. The last option is imme-

diately upon obtaining a negative pregnancy test.

Some combination therapies include antibiotics. Antibiotics

and birth control pills can be used safely; however, of all the

interactions that have been reported, 76% involve rifampin.

Rifampin is a potent inducer of cytochrome p450, which

increases metabolism of oral contraceptives and other med-ications. The hypothesis with antibiotic use is antibiotics

decrease the gut flora that are needed to further degrade

inactive metabolites of the oral contraceptives to active drug

during enterohepatic recirculation. This theory has never been

substantiated. Two studies in the dermatology literature look

at pregnancy rate in women who are on birth control pills and

antibiotics. The pregnancy rate was not statistically different

between women who were on both versus women who were

on a birth control pill alone (1.6% versus 0.96%).

CONCLUSION

Oral contraceptives prescribed eff e c t i v e l y, safely and eff i c i e n t l ywill greatly impact the quality of life of women with acne.

References

1. Hersh EV. Adverse drug interactions in dental practice: interactions involv-

ing antibiotics: part II of a series. J Am Dental Assoc . 1999;130(2):236–251.

2. London BM, Lookingbill DP. Frequency of pregnancy in acne patients tak-

ing oral antibiotics and oral contraceptives. A rch Derm a t o l .1994;130(3):392–393.

Exhibit area at the Fall Clinical Dermatology Confere n c e®.



fallclinical_march08

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