Download PDF - The Dermatologist

Supplement to the March 2008 

skin 

&AGING 

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.

FA L L C L I N I C A L D E R M AT O L O G Y C O N F E R E N C E P R O C E E D I N G S 

FALL CLINICAL 

DERMATOLOGY 2007 

AN UPDATE ON ADVANCES IN ACNE AND EXCERPTS FROM 

WHAT’S NEW IN THE MEDICINE CABINET 

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

DERMATOLOGY RESIDENCY DIRECTOR 

VALLEY HOSPITAL MEDICAL CENTER 

LAS VEGAS, NV 

Acne vulgaris is one of the 

most common diagnoses 

e n c o u n t e red in clinical 

practice. Most advances relate to 

i m p rovements in vehicle technology 

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- 

James Q. Del Rosso, 

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

ACNE UPDATE 

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 ability 

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 tetracycline. 

Benzoyl peroxide, including formulations that also 

contain clindamycin, is well established for reducing inflammatory 

acne lesions but also for decreasing non-inflammatory 

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

Multiple clinical trials have evaluated tretinoin (Retin-A 

M i c ro, Tretin-X, Atralin), 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 vehicles 

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 vulgaris 

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 adapalene 

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

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 therapy 

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

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. 

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-inflammatory 

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 once 

daily 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 

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


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 “convenience 

value.” A recent study evaluating the use of 

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

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 and 

symptoms 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 twot 

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 noninferior 

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 clindamycin 

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 superior 

efficacy 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, moderate, 

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 formulation” 

(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 demonstrated 

efficacy in clinical studies with a very favorable tolerability 

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 in 

the 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 system 

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 combined 

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 secondary 

to increased local androgen production within sebaceous 

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 hormonef 

ree days, resulting in a short menstrual cycle. In a placeboc 

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). 

ACNE APPEARS TO OCCUR 

SECONDARY TO INCREASED LOCAL 

ANDROGEN PRODUCTION WITHIN 

SEBACEOUS GLANDS. 

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 benefits 

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. 



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 minocycline 

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

THERE IS NO SCIENTIFIC 

EVIDENCE THAT PILL SPLITTING 

OF ANY TABLET FORMULATION OF 

DOXYCYCLINE PRODUCES 

ANTI-INFLAMMATORY ACTIVITY 

WITHOUT AN ANTIBIOTIC EFFECT. 

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 as 

c o m p a red to immediate-release minocycline formulations. 

Results from Phase II and Phase III trials substantiate therapeutic 

equivalence for acne vulgaris with extendedrelease 

minocycline when dosed at 1 mg/kg/day as comp 

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

markedly 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 FDAa 

p p roved for treatment of rosacea. There is no scientific evidence 

that pill splitting of any tablet formulation of doxycycline 

p 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 antiinflammatory 

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 activity 

of several matrix metalloprotease enzymes (MMPs). Antiinflammatory 

dose doxycycline offers advantages over conventional 

oral antibiotic therapy. These include efficacy with a favorable 

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 evaluating 

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 subjects 

who were actively treated in the pivotal Phase III studies. 



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 nasopharyngeal 

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 twicedaily 

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 compliance 

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-inwater 

formulation that has been used for more than 3 decades 

in 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, dermal 

ulcers, radiation dermatitis, minor abrasions, actinic keratosis 

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 radiotherapy 

because the modalities could be administered simultaneously 

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 bacitracin 

because the latter 2 agents are well recognized as common 

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 extendedrelease 

formulation of minocycline hydrochloride tablets. Cutis. 2006;78(4 

Suppl):6–10. 

3. Fleischer AB Jr, Dinehart S, Stough D, et al. Safety and efficacy of a new 

e x t e n d e d - release formulation of minocycline. 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 III 

clinical trials evaluating anti-inflammatory dose doxycycline (40-mg doxycycline, 

USP capsules) administered once daily for treatment of rosacea. J Am 

Acad 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 Clinical 

Dermatology 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 contro l l e d - release capsules) and 

metronidazole 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 gel 

15% once daily versus twice daily in the treatment of rosacea. Presented at 

the World Congress of Dermatology in Buenos Aires, Argentina, October 

1–5, 2007. 

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

11. Del Rosso JQ, Tanghetti E. The clinical impact of vehicle technology 

using a patented formulation of benzoyl peroxide 5%/clindamycin 1% gel: 

comparative assessments of skin tolerability and evaluation of combination 

use 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 versus 

tazarotene plus clindamycin/benzoyl peroxide in the treatment of acne vulgaris: 

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 vulgaris. 

Submitted for publication 2008. 

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

applications in dermatology. Cutis. In press. 

16. Broughton G 2nd, Janis JE, Attinger CE. The basic science of wound 

healing. Plast Reconstr Surg. 2006;117(7 Suppl):12S–34S. 



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 

There have been few, if 

any, new systemic or topical 

medications developed 

in the last few years for the 

treatment of rosacea, so oftentimes, 

advancement in therapy 

relies upon the correct diagnosis. 

The right medicine will not work 

with the wrong diagnosis. For 

Joseph Bikowski, M.D. every individual who pre s e n t s 

with a red, scaly face, the dermatologist 

will consider the differential diagnoses: rosacea, seborrheic 

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 forehead, 

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 scaling 

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 individual 

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. 

PATIENTS IN WHOM THE DIAGNOSIS 

OF ROSACEA IS SUSPECTED SHOULD 

HAVE KOH PREPARATIONS 

PERFORMED ON SCRAPINGS OF THE 

SCALES FROM THEIR FACES. 

Plaque ro s a c e a . The usual presentation for rosacea is erythema, 

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 isolated 

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. 



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

METHRIN TWICE DAILY (RIGHT). 

BASELINE 

AFTER 2 WEEKS 

U S U A L THERAPIES FOR ROSACEA 

van Zuuren et al 1 conducted a literature review of 71 randomized, 

controlled studies of rosacea therapy. Of the 71 

studies, 29 met their inclusion criteria, but the quality in general 

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 evidence 

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, cont 

rolled trials examining the efficacy of present medications for 

the treatment of ro s a c e a . 

Del Rosso et al 2 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 diseases, 

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 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. 

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

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-thecounter 

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, especially 

rosacea, should be encouraged to purchase one of 

these products as a cleanser and a moisturizer. 

THERE IS AN INCREASED INCIDENCE 

OF ROSACEA PATIENTS WITH 

MIGRAINE HEADACHES. BOTH 

ROSACEA AND MIGRAINES ARE 

VASCULAR DILATATION PHENOMENA. 

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. 

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 challenge, 

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 erythema. 

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 r 

options for treating the erythema of rosacea are water- b a s e d 

emulsions or nonsteroidal creams. In a patient who has persistent 

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 colleagues 3 at the University of 

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

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 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 

and stratum corneum tryptic enzymes, which lead to 

abnormal peptides and the signs and symptoms of 

rosacea. They discovered increased levels of cathelicidin 

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. 

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

versus those who do not have rosacea, and these peptides 

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 counter 

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

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

dermatologists new treatment options in the future. 

References 

1. van Zuuren EJ, Gupta AK, Gover MD, Graber M, Hollis S. Systematic 

review 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 doxycycline, 

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 activity 

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


TREATING ACNE WITH ORAL 

CONTRACEPTIVES 

A GUIDE FOR SAFE, EFFECTIVE AND EFFICIENT PRESCRIBING 

BY JULIE C. HARPER, M.D. 

UNIVERSITY OF ALABAMA – BIRMINGHAM 

BIRMINGHAM, AL 

While some dermatologists 

have been prescribing 

oral contraceptives 

for the treatment of acne 

for many years with much success, 

others are resistant. The 

goal of this article is to assure the 

safe, effective and efficient prescription 

of oral contraceptives for 

acne patients, which will result in 

Julie C. Harper, M.D. 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 armamentarium 

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 inflammation. 

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 secondary 

to P. acnes 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 micrograms 

to 50 micrograms in a pill. The amount of ethinyl estradiol 

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, levonorgestrel, 

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 hormone 

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 ovary 

produces less androgen. 

The novel progestin, dro s p i renone, is equivalent 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 antimineralocorticoid 

properties as well. 

Attendees focus on new clinical information. 



Attendees learning the latest in the field. 

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 contraceptives 

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 number 

one conclusion is it is difficult to compare trials because 

investigators in acne studies do not always use the same stand 

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 the 

sex 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 management 

of acne is dro s p i renone 3 mg and ethinyl estradiol 

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% reduction is an impressive change. 

ORAL CONTRACEPTIVE RISKS 

One reason dermatologists may not prescribe oral contraceptives 

for their acne patients is the risks associated with 

birth control pills. These risks include venous thromboembolism, 

stroke, myocardial infarction and breast cancer. 

Venous thromboembolism. The risk of venous thromboembolism 

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 factors, 

such as cigarette smoking, hypertension and migraine 

headaches, are present. 

Myocardial infarction. Eighty percent of myocardial infarctions 

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 metaanalysis 

looked at more than 53,000 women with breast cancer 

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


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

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 menstrual 

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 properties, 

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 treatment 

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

necessary to increase the ethinyl estradiol dose and prescribe 

a different pill. Irregular bleeding is one side effect that worsens 

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 pregnancy; 

current breast cancer; breast feeding; age over 35 and 

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

diabetes with nephropathy, retinopathy, neuropathy, and vascular 

disease; deep vein thrombosis, history or current; history 

of heart disease; history of stroke; and migraine headaches 

with focal neurological symptoms at any age or without neurological 

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 immediately 

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 medications. 

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 y 

will greatly impact the quality of life of women with acne. 

References 

1. Hersh EV. Adverse drug interactions in dental practice: interactions involving 

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 taking 

oral antibiotics and oral contraceptives. A rch Derm a t o l. 

1994;130(3):392–393.

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