A Cmd Supplement Final

skin&AGING

SUPPLEMENT TO THE OCTOBER 2007

SUPPLEMENT PROCEEDINGS FROM THE

ADVANCES IN COSMETIC &MEDICAL DERMATOLOGY

“MAUI DERM” 2007 CONFERENCEARTICLES IN THIS SUPPLEMENT ARE BASED ON SELECTED PRESENTATIONS

FROM THE ADVANCES IN COSMETIC & MEDICAL DERMATOLOGY “MAUI DERM” 2007 CONFERENCE

HELD JANUARY 17-22, 2007, IN MAUI, HAWAII.

CURRENT CONCEPTS IN THE IMMUNOLOGYOF CUTANEOUS DISEASESNEW DEVELOPMENTS IN PSORIASIS.BY ANDREW BLAUVELT, M.D.

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PEDIATRIC DERMATOLOGY DIAGNOSTIC AND TREATMENT TIPSFOR CHALLENGING PEDIATRIC CASES.BY SHEILA FALLON FRIEDLANDER, M.D.,AND LAWRENCE EICHENFIELD, M.D.

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STRATEGIES IN ACNE ANDACNE ROSACEA MANAGEMENTHIGHLIGHTS OF THE ACNE SYMPOSIUM AT ACMD 2007.PRESENTED BY GUY WEBSTER, M.D., PH.D.,LAWRENCE EICHENFIELD, M.D., AND ALAN SHALITA, M.D.

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CHEMOPREVENTIONITS ROLE IN DERMATOLOGY TREATMENTS.BY TED ROSEN, M.D., MICHAEL H. GOLD, M.D., AND WM. PHILIP WERSCHLER, M.D., F.A.A.D., F.A.A.C.S.

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FACES AND FILLERSAN OVERVIEW AND A DISCUSSION OF POSSIBLE COMPLICATIONS AND TIPS ON AVOIDING THEM.BY SANDY TSAO, M.D., AND JOEL L. COHEN, M.D.

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THE MIDDLE GROUNDTHE OPTIONS BETWEEN ABLATIVE TREATMENTS AND NONABLATIVE LASER THERAPIES.BY SUZANNE L. KILMER, M.D.

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ETHICS IN MEDICINEWHAT YOU NEED TO KNOW IN DAY-TO-DAY PRACTICE.BY GEOFFRY ANDERS, J.D., C.P.A., C.H.B.C.

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CONTENTS

HMP COMMUNICATIONS

EDITORIAL STAFFSPECIAL PROJECTS EDITORSTEFANIE TULEYA

EXECUTIVE EDITORLARISA HUBBS

SENIOR EDITORELLEN MEYER

DESIGN AND PRODUCTIONART DIRECTORKAREN COPESTAKES

CREATIVE DIRECTORVIC GEANOPULOS

PRODUCTION DIRECTORKIM CHESKY

PRODUCTION MANAGERTRISH MORRIS

BUSINESS STAFFPUBLISHER JEREMY BOWDEN

NATIONAL SALES MANAGERPHIL LEBRESCO

PROJECT MANAGERLINDSAY MAZZAGATTI

CIRCULATION MANAGERBONNIE SHANNON

83 GENERAL WARREN BLVD, SUITE 100, MALVERN, PA 19355

(800) 237-7285 • (610) 560-0500FAX (610) 560-0501

DEAR READERS,

The annual meeting of Advances in Cosmeticand Medical Dermatology — “Maui Derm”

— continues to establish itself as one of thekey educational events in dermatology. Createdas a meeting for “thought leaders”, ACMD pro-vides attendees with in-depth, cutting-edge and,at times, controversial lectures, panel discus-sions and workshops relevant to our daily prac-tice of both medical and cosmetic dermatology.For those who were unable to attend January’smeeting, several of our faculty have providedthe highlights of their discussions.

In this supplement, Dr. Andy Blauvelt reviews the latest conceptsin cutaneous immunology, which are relevant to understanding pso-riasis and blistering diseases. Two eminent pediatric dermatolo-gists, Drs. Sheila Fallon Friedlander and Larry Eichenfield discusstheir approaches to challenging pediatric cases. Dr. Guy Webstersummarizes the latest recommendations from the panel of acneand rosacea experts. Drs. Michael Gold, Ted Rosen and PhilWerschler review their strategies in treating actinic keratoses. Theincreasing use of dermal fillers is not without risk and in their arti-cle, Drs. Joel Cohen and Sandy Tsao provide their suggestions foravoiding and managing complications when they occur. Dr. SuzanneKilmer shares her experience and knowledge of both plasma kinet-ic and fractional resurfacing as the “middle ground” in skin resur-facing. In the final article, Geoff Anders utilizes his 25 years ofexperience as a medical malpractice attorney and consultant indiscussing the thought provoking topic of medical ethics.

I hope that you will enjoy and benefit from these articles. Please joinus at ACMD “Maui Derm” in 2008.

Thank you,

GEORGE MARTIN, M.D.

LETTER

George Martin, M.D.

In the past year, there have been many exciting develop-ments in the areas of immunology and dermatology, someof which will be highlighted in this article.It is well known that psoriasis is a T-cell mediated dis-

ease. Many of the biologic therapies that have beendeveloped in the past 10 years target T cells and theirassociated cytokines that are abnormal in psoriasis.Histologically, a large num-ber of T cells are foundwithin the dermal papillaeand the upper parts of thedermis, and fewer scat-tered T cells are foundwithin the epidermis.

By contrast, in normalhuman skin there are no Tcells present in the epider-mis. In the dermis, onlyscattered lymphocytes arepresent, and they are notalways easily recognized byroutine histology. Antigenpresenting cells, mainlydermal dendritic cells, aregreatly increased in num-ber in psoriasis as well.The major function ofthese cells is to stimulate T cells.

PSORIASIS: A TH1 DISEASE?It has been taught for many years that psoriasis is a

Th1 disease. Th1 cells are T helper cells that aredefined by the cytokines they make. In psoriasis, it isknown that Th1 cells are present in affected skin, andthere is abundant interferon-γ made by these cells. Thisknowledge contributed to the existing paradigm that pso-

riasis is a Th1 disease because of the presence of thesecells, and because of the relative absence of Th2 cellsthat make interleukin (IL) 4.

In the last 5 years, a new type of T cell has beendescribed called the Th17 cell, and it secretes a differ-ent pattern of cytokines distinct from Th1 and Th2 cells.It is called “Th17” because it secretes IL-17

as one of its main cytokines, which is a pro-inflammatory cytokine.

Interestingly, many dis-eases that were previouslybelieved to be classic Th1diseases have recentlybeen reclassified as Th17diseases, according toleading immunologists.These diseases includeCrohn’s disease, rheuma-toid arthritis, multiple scle-rosis and psoriasis.Involved tissue in thesediseases contains bothTh1 cells and Th17 cells. Itis now believed that Th1cells are probably servingto counter-regulate or

dampen inflammation caused by Th17 cells. Thus, fol-lowing the discovery of Th17 cells, the presence of Th1cells in affected tissue in the absence of Th2 cells doesnot equal “Th1 disease” anymore.

This is important because it opens up a whole differ-ent pathway of targets for new therapies. Compared toTh1 cells, different molecules are involved in the devel-opment and proliferation of Th17 cells. New treatmentsare aimed now at blocking the development or prolifera-

BY ANDREW BLAUVELT, M.D.

CURRENT CONCEPTS IN THE IMMUNOLOGY OFCUTANEOUS DISEASES:NEW DEVELOPMENTS IN PSORIASIS.

If psoriasis is predominantly a “Th17 disease,” as

recent scientific evidence suggests, then targeting the protein subunit that

is specific for IL-23,called p19, would be the best approach.

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A D VA N C E S I N C O S M E T I C & M E D 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

tion of Th17 cells. One example of a new target is IL-23,which is the major cytokine that makes Th17 cells sur-vive and grow. Thus, IL-23 has become a key target forpsoriasis and other related autoimmune inflammatorydiseases as mentioned above.

IL-12 is the main cytokine that makes Th1 cells grow, and,as mentioned, IL-23 is the main cytokine that makes Th17cells grow. These two related cytokines share a commonprotein subunit called p40. When trying to target both Th1and Th17 cells, p40 would be an attractive target. If psoria-sis is predominantly a “Th17 disease,” as recent scientificevidence suggests, then targeting the protein subunit that isspecific for IL-23, called p19, would be the best approach.

The more we learn about psoriasis pathogenesis, themore we can start thinking about specific targets to treat it,and also how to avoid side effects. For example, we wouldnot want to target Th1 cells if they were counter-regulatingTh17 cells, especially since Th1 cells are important inmounting normal immune responses to pathogens.

PSORIASIS: A TH17 DISEASEA large amount of recent data, beyond the scope of this

article, suggests that psoriasis is a Th17 disease. In psori-atic skin, the best, most recent evidence shows that IL-23 is

up-regulated, whereas IL-12 is not elevated. Levels ofTh17 cytokines, especially IL-17 and IL-22, are alsoincreased in psoriatic skin. IL-23, IL-17 and IL-22decrease as psoriasis clears with effective therapy.Recent genetic studies have shown polymorphisms in theIL-23 subunit, p40 and in the IL-23 receptor (IL-23R)linked to psoriasis susceptibility.

Transgenic mouse studies show that over-expressionof p40 in mouse skin leads to inflammatory skin dis-ease. Furthermore, directly injecting IL-23 into normalmouse skin leads to psoriasis-like inflammation, where-as IL-12 injections do not cause this same effect. Inthese mouse studies, the Th17 cytokine IL-22 is criticalin causing keratinocytes to proliferate. Finally, trans-genic mice that over-express TGF-β1 or Stat3 in skin alsodisplay features of psoriasis. This is important becausethese proteins are involved in Th17 development, butnot Th1 cell development.

CLINICAL TRIALSNew scientific research advances can lead to develop-

ment of new treatments for patients. It is known that TNF-αis an important cytokine in psoriasis, and we now know thatTNF-α also is produced by Th17 cells. Although TNF-α is

S U P P L E M E N T T O S K I N & A G I N G • O C T O B E R 2 0 0 7 • 5

Fig 1. Th17 cells are distinct from Th1 and Th2 cells.

Th1 = IFN-γ, IL-2

Th2 = IL-4, IL-5, IL-10

Th17 = IL-17A, IL-17F, IL-22

made by many additional cell types, it is interesting to spec-ulate that TNF-α blockers could be working in part by block-ing Th17 cell production of TNF-α.

A number of new agents are under investigation thattarget key proteins in the IL-23/Th17 cell inflammatorypathway. Monoclonal antibodies that inhibit p40, theprotein subunit common to IL-23 and IL-12, have beendeveloped by at least twocompanies. Initial Phase IIresults have shown dra-matic clinical effects inpatients with moderate-to-severe psoriasis. This sug-gests that p40 is an excel-lent target in psoriasispatients; however, interfer-ing with Th1 cells may leadto unwanted side effects. Thus far, short-term use ofanti-p40 monoclonal antibodies has not caused anymajor adverse effects, but has shown tremendous effi-cacy. Long-term safety and efficacy of anti-p40 mono-clonal antibodies in patients with moderate-to-severepsoriasis is currently under study. The dermatologycommunity will be anxiously awaiting the results fromthese studies.

LOOKING AHEADTh17 cells are a new type of T cell distinct from Th1 and

Th2 cells. It is now believed that Th17 cells are key mediatorsin a variety of autoimmune inflammatory diseases, includingpsoriasis. IL-23 is a master cytokine regulator for these dis-eases, since it is the cytokine that stimulates survival and pro-liferation of Th17 cells. Recent basic science studies in this

area are translating into devel-opment of new therapies forpsoriasis that target key pro-teins in the IL-23/Th17inflammatory pathway.

Dr. Blauvelt is a Professor in

the Department of Dermatology

and the Department of

Molecular Microbiology and

Immunology at Oregon Health & Science University in Portland, OR.

FURTHER READING 1. Blauvelt A. New concepts in the pathogenesis and treatment ofpsoriasis: key roles for IL-23, IL-17A and TGF-β1. Expert RevDermatol. 2007;2:1-10.

2. Krueger GG, Langley RG, Leonardi C, et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl JMed. 2007;356:580-592.


It is now believed that Th17cells are key mediators in a

variety of autoimmune inflammatory diseases.

Fig 2. Schematic showing primary role of IL-23 and Th17 cells as key mediators in psoriasis pathogenesis.

CD8+ T cells

Langerhans cells (LC)

CD4+ T cells

Non-LC mature epidermaland dermal dendritic cells

Epidermis

Dermis

Non-LC dendritic cellsand keratinocytes IL-23

CD4+ T cells(?CD8+ T cells)

IL-17AIL-17FIL-6TNF-αIL-22*

IL-19IL-24 keratinocyte proliferation

keratinocyte activation

Treating pediatric dermatology patients can be chal-lenging. These pediatric dermatology experts sharediagnostic and treatment tips on conditions that they

regularly treat in practice. Touching on topics such ashemangiomas and atopic dermatitis, they offer importantdiagnostic tools and their favorite treatment options.

HEMANGIOMAS: WHEN TO WORRYWhen examining a patient with a hemangioma, location is

one of the single-most important things to consider. Is it alesion that can obstruct? Will it be subject to friction? Is it mid-line? Also, consider the pattern of the hemangioma.Segmental hemangiomas are higher risk. More than six orseven lesions raises the possibility of internal organ involve-ment. Age is another important consideration. If a parentbrings in a 4 year old who has a lesion that stopped growing 3 years ago, it’s not as worrisome as a 2 month old who hasa lesion close to the eye that is still growing.

Results from a study that looked at more than 1,000hemangiomas in approximately 1,000 children was recentlypublished in Pediatrics.1 The researchers confirmed long-held suspicions that large lesions, segmental lesions andfacial lesions are the ones that are more likely to be asso-ciated with a more complicated, worrisome course.

Gold standard treatment approaches.2 Most of the lesionsdo not need to be treated. If treatment is required, systemicsteroids are still the gold standard choice. As far as pred-nisolone treatment, Orapred 15 mg/5 cc tastes better, andgenerally patients will respond to 2 to 3 mg/kg/day, usually asa once-a-day morning dose. The course of treatment is oftenmonths rather than weeks, but the sooner one can success-fully taper, the better. Unfortunately, early taper can be associ-ated with rebound growth of these vascular growths. Be sureto monitor blood pressure and growth, and make the familyaware that the child is on a medicine that can interfere with theimmune system response to infections. Live vaccines are not

recommended while on treatment. If a patient being treated isexposed to varicella, the parents must inform the dermatolo-gist, and most experts would treat this child with systemic acyclovir (Zovirax). Also, reports have surfaced of pneumocys-tis in children treated with systemic steroids, and a few expertsprophylax all patients on systemic steroids with oral trimetho-prim sulfa (Tribrissen, Septra, Bactrim, Cotrim, Sulfatrim) forthis reason. Protect the stomach from the risk of gastritis withan H2 blocker such as ranitidine (Zantac).

Other treatment options for hemangiomas include topicalclass 1 steroids, intralesional corticosteroids and laser treat-ments. For difficult-to-treat hemangiomas, referral to a spe-cialist is recommended. Other options, which possess signifi-cant side effects, include interferon alpha 2a or 2b (1 to 3 million units SC/m2 daily; risks include spastic diple-gia) and vincristine (Oncovin) (1 mg/m2 IV weekly/taper prn).3

MORE THAN MEETS THE EYEAt times, hemangiomas can represent more than meets

the eye. For example, a 3-month-old baby presents withnumerous hemangiomas. They are tiny and don’t appear wor-risome — there is no ulceration. The pediatrician referredjust to be sure there was no cause for worry.

When a child presents with multiple hemangiomas of anysize — more than five to seven — the possibility of systemicinvolvement must be considered. First of all, a careful physi-cal examination must be completed. Feel the liver. Is thereany evidence of enlargement? If a child presents with a largenumber of lesions, evaluation should include a liver ultra-sound, a complete blood cell count to rule out anemia, and astool heme test to rule out bleeding within the gut.

If a patient presents with a large, facial hemangioma, con-sider PHACES.4 When considering PHACES, look for Posteriorfossa anomalies, Hemangiomas, Arterial anomalies particular-ly in the neck and the head, Cardiac anomalies, Eye findings,and Sternal clefts as well as supraumbilical abdominal raphes.

BY SHEILA FALLON FRIEDLANDER, M.D., AND LAWRENCE EICHENFIELD, M.D.


PEDIATRIC DERMATOLOGYDIAGNOSTIC AND TREATMENT TIPS FOR CHALLENGING PEDIATRIC CASES.


When examining large, facial hemangiomas, perform agood physical exam and refer to an ophthalmologist for acomplete eye exam. Cardiac examination is important, andbe certain to obtain an echocardiogram. Also, consider anMRI/MRA on these patients. And, be aware of long-termCNS vasculo-occlusive risks that are present; some childrenappear to acquire CNS vascular abnormalities over time andhave an increased risk for stroke.5

Other types of hemangiomas to be concerned aboutinclude beard area hemangiomas. Hemangiomas that pres-ent in a “beard distribution” may be a marker for underlyingairway hemangiomas that can cause respiratory compro-mise. Short courses of oral steroids may transiently improvethe condition, but can lead to a delay in diagnosis.6

Another area of presentation that should raise concern isthe midline because sometimes hemangiomas are evidenceof spinal diastrophism, particularly if there is a lipoma or anyother cutaneous finding present in the lower lumbosacralarea. In the first 3 months of life, an ultrasound can be usedas a gross screen, and is especially helpful if one can observefree movement of the lower spinal cord (cauda equina) withinthe spinal column on respiration. After 3 months of life, anMRI is required. Children with lumbosacral hemangiomas, par-ticularly those with associated findings, such as a lipoma ortuft of hair, are at increased risk for spinal dysraphism, includ-

ing tethered cord. If identified early, patients can have surgeryto prevent neurological dysfunction. You, the dermatologist,can be a real hero in such cases!

Ulcerated hemangiomas should also raise concern. Expertsnow recommend starting treatment with saline compresses,topical antibiotics and occlusive dressings. This is a good placeto start, but often is not enough. Other treatments includepulsed-dye laser therapy, systemic intralesional steroids, exci-sion or 0.01% becaplermin (PDGF) topical therapy.7-10

The study of hemangiomas is now an ongoing area of sig-nificant research interest. They are fascinating lesionsbecause they are vascular tumors that rapidly grow and thenabruptly stop. Microarray analysis is a research tool that hasrecently been utilized to evaluate hemangioma tissue. This isan indiscriminate means of identifying factors of interest. Itsimultaneously analyzes tens of thousands of genes as ameans of identifying specific genes for further study. It helpsdetermine what genes are up-regulated, what RNA message isout there, and what proteins and enzymes are being producedin certain lesions. An increased up-regulation of insulin-likegrowth factor in proliferating hemangiomas has been found.11,12

Currently, a lot of excitement centers on the placenta, orcells that are similar to placental cells, as the etiology forhemangiomas in children and risk groups. And there is asuggestion that women who have had placental insufficien-cy might be at a higher risk for having children with heman-giomas. Researchers performed a micro-array analysis look-ing at hemangioma tissue in comparison to placental tissueand found that they were very similar.13 We, at Children’sHospital San Diego, are currently utilizing such methods toverify if there is a relationship between placental character-istics and function and risk for hemangiomas in children.

One suspicion is that placental cells embolize to the fetusand then proliferate in the infant’s skin. There is no evidencethat maternal microhimerism is present, so it is unlikely thathemangiomas represent embolism of maternal tissue; how-ever, the placenta is almost completely fetal in origin.14

TINEA CAPITISTinea capitis is predominantly caused by Trichophyton

tonsurans in the United States. Therapeutic results with thenewer agents, oral fluconazole (Diflucan) and standard-doseterbinafine (Lamisil) have been mixed. It’s not so clearwhether they’re better than griseofulvin (Fulvicin, Grifulvin,Gris-PEG), but recently a large multi-center study was com-pleted on the efficacy of terbinafine mini-tablets at higherdosing compared to high-dose griseofulvin. The results arepromising, and we’re very optimistic now regardingterbinafine in the treatment of tinea capitis.


Fig 1. Patient with PHACES syndrome with a large,plaque-like segmental facial hemangioma. Photo courtesy of Elena Pope, M.D., M.Sc., FRCPC.


It’s important to culture children who you think have tineacapitis, and don’t forget about young children and the associ-ation of tinea with cats. A small number of cases in young chil-dren are caused by Microsporum canis transmitted by cats or,rarely, by dogs. At this particular time, high-dose griseofulvin (20 to 25 mg/kg/day micro) with food for at least 6 weeks isconsidered the gold standard treatment. Recheck patients at 4 weeks and prolong therapy as needed. No labs are neededas long as therapy is less than or equal to 8 weeks. Topicalanti-fungal lotions and shampoos are thought to be helpful indecreasing the time of infection. Also, consider off-label use ofhigher-dose terbinafine 4 mg/kg/day to 8 mg/kg/day for 4 weeks, particularly if griseofulvin fails.

ONYCHOMYCOSISOnychomycosis, although more common in adults, does

occur in pediatric patients. Traditional evaluation consists ofKOH and culture. Other options include calcofluor and chlo-razole black and PAS. Studies have shown that PAShistopathological evaluation in combination with culture is thebest way to make the diagnosis, but it is more expensive.15

When it comes to treating children with onychomycosis,many options exist, but there is no ideal, extremely effective,quick and perfectly safe option.

Treatments to consider include:16

• Ciclopirox, amorolfine lacquer, bifonazole-urea• Griseofulvin 20/kg for at least 6 months; don’t exceed

1 gram• Terbinafine 5 mg/kg/day; don’t exceed 250 mg;

FN 6 weeks; TN 12 weeks• Fluconazole 6 mg/kg/week once a week; FN 12 weeks;

TN 26 weeks• Itraconazole caps 5 mg/kg/day pulse therapy; FN 2

pulses; TN 3 pulses.It has been hypothesized that children might do better with top-

ical agents than adults because children’s nails may grow faster.That’s controversial, but a child’s nail plate certainly is thinnerthan an adult’s, and healthy children have better peripheral circu-lation than those older individuals suffering from diabetes or ath-erosclerois. Children are less likely to have total dystrophic infec-tion and more likely to have sparing of the nail matrix.16,17

A prospective, double-blind, randomized, pilot study wasconducted to evaluate the use of topical ciclopirox 8% lac-quer for toenail infection, which does not involve the nailmatrix.18 All study participants were 2 to 16 years of age andall had culture-proven dermatophyte infection. The resultsare promising, and raise the possibility that children may dobetter than adults with topical therapy if they have limiteddisease that does not involve the matrix.

CONGENITAL NEVIThe incidence of small congenital lesions (1%) is more

common than giant lesions, which, fortunately, are not allthat common (1 in 20,000). With giant congenital nevi, therecan be a cosmetic issue, but more important than the cos-metic issue are the medical issues, such as malignantmelanoma and neurocutaneous melanosis.18

Determining what constitutes a giant congenital nevus isthe first step in determining risk. Although there is probablya continuum of risk that increases with increased density andamount of melanocytes present, it is hard to determine“melanocyte burden” and easier to think of those childrenwith the largest lesions as those with the greatest risk. It canbe difficult to determine which of these lesions are large con-genital melanocytic nevi (LCMN) at birth. In adults, a lesionthat is >20 cm diameter or >5% body surface area is con-sidered a LCMN. When looking at infants at birth, a lesionthat is at least 9 cm in diameter on the head or 6 cm to 7 cm in diameter on the body is considered a LCMN becausehead lesions increase by 1.5 and body lesions by 3.19,20

When examining a patient with a congenital nevus,the one question families really want answered is: Whatis the risk of melanoma? Results from studies vary, butin a recent publication, small lesions appeared to havea risk of 0.5% post-puberty. However that risk rises to4.11% for large lesions. In children with LCMN, themost important risk factors for melanoma are largenumbers of satellite nevi, as well as increased mediandiameter of LCMN (49 cm vs. 39 cm).21


Fig 2. Patient with congenital melanocytic nevi. Photo courtesy of Miriam Weinstein, M.D.

ATOPIC DERMATITISFilaggrin gene abnormalities are associated with barrier

dysfunction, and were also shown to be a very high risk fac-tor for atopic dermatitis. Mutations in the filaggrin gene areassociated with ichthyosis vulgaris. It has been shown that10% of people of European ethnicity have the loss-of-func-tion mutation for filaggrin, which is a strong predisposingfactor for atopic dermatitis, asthma secondary to atopic der-matitis and allergic sensitization (high IgE).22,23 However, it’simportant to note that this mutation is not the answer to allof atopic dermatitis; it’s just a subset of patients who havethis barrier dysfunction — this genetic tendency.

The question is: Which is first in atopic dermatitis —inflammatory dysregulation or barrier dysfunction? It isintriguing that in at least a subset, but not the majority ofatopic dermatitis patients, this mutation is responsible foran abnormality that may have an impact on inflammation.

Our current concept of atopic dermatitis still deals withimmunodysregulation. Clearly, there is increased activity ofinflammatory cells, Langerhan cells and the inflammatorydendritic cells. We know that there’s been work on T cells,but not as much the T-cell subsets other than the inflam-matory dendritic cells, and we’re still left with a sense thatthere’s an immunodysregulation in eczema that may be dif-ferent from the barrier dysfunction.24

Over the course of time, we’ve learned that if you look ata population of patients with atopic dermatitis, the course oftheir diseases is incredibly variable. Disease-based severity

requires a severity assessment, and severity assessment isnot just how bad the eczema looks when you see it at theone point in time at the office, because a course of atopicdermatitis is tremendously variable.

If you look at the general population of atopic dermatitis inchildren, about 40% likely have very, very intermittent disease.After a patient has had a flare, if it is controlled, the patientmay be maintained very well with just moisturizer alone. Onthe other hand, in our practice, we routinely ask families:When’s the last time your child’s skin was totally clear ofeczema? About 40% of those families say “never.” The patientwho has persistent and/or frequently recurring eczema is adifferent kind of patient to take care of than the patient withintermittent disease. The persistence of a patient’s diseasewill influence treatment and maintenance regimens.

PRODUCTS FOR ATOPIC DERMATITISWhen used after emollients at the first signs or symptoms

of dermatitis, the vehicle arms from the core clinical studiesfor pimecrolimus (Elidel) and tacrolimus (Protopic) haveallowed 35% of infants and children to go 6 months withouta corticosteroid or with a recorded flare. Also, when used formoderate-to-severe atopic dermatitis, the vehicle arms forthese studies allowed 27% to be at least 50% improvedafter 12 weeks of therapy.25-27

In many studies of infants, children and adults with topi-cal pimecrolimus, 30% to 35% of patients who received justthe cream without the pimecrolimus went 6 months withouta flare and without topical corticosteroids. These resultsshow us that a subset of the population can be maintainedwith moisturizers alone. These patients have either easilyremitted atopic dermatitis or disease that is not often flar-ing. And even in the moderate-to-severe population, 27% ofthe patients got 50% better with just vehicle.

New barrier creams have recently been added to our treat-ment regimens. Many of the creams have been approved as510K devices — the application process that the FDA hasallowed for device approval as compared to prescriptiondrug approval. This means many of these products havebeen approved before large numbers of patients were stud-ied in clinical studies, but there appears to be efficacy tothese products in terms of repairing the skin barrier and hav-ing an anti-inflammatory effect.

The trickier question regards how you treat a patient withmore inflamed atopic dermatitis and persistent disease. It’simportant to separate acute intervention from maintenancetherapy. For acute intervention you need the appropriatestrength medicine, topical corticosteroids being the main-stay. Short term, we may recommend very strong high-poten-

1 0 • O C T O B E R 2 0 0 7 • S U P P L E M E N T T O S K I N & A G I N G

Fig 3. Topical calcineurin inhibitors have been used off-labelwith success in treating patients under 2 years of age foratopic dermatitis. Photo courtesy of Dr. Manisha Patel.


cy topical corticosteroids, even in pediatric patients. We willalso use wet wrap therapy with topical corticosteroids —generally a bathing, double-wrap therapy where you take apatient out of the bath and apply a steroid, followed bywraps in wet and dry gauze wraps. If that patient is 90% bet-ter to 100% better within 2 to 3 weeks of aggressive inter-vention, we then need to determine the best course of main-tenance therapy, which is typically intermittent topical corti-costeroids and intermittent topical calcineurin inhibitors. Wehave some patients in our practice whose maintenance ther-apy includes twice-a-day application of the most potent topi-cal calcineurin inhibitor and 2- to 3-time-per-week applicationof a topical corticosteroid. These are patients who haveworked up to that maintenance therapy because without itthey have too much disease burden.

MANAGING EXPECTATIONSAnother very important aspect to atopic dermatitis thera-

py is to modify family expectations because, again, 40% ofparents claim that their children are never clear of disease.It’s important to convince families to accept that it’s okay tohave a little disease. Tell families not to expect that eachand every scale will be gone, or each and every area of red-ness will be alleviated — the goal of therapy is to bring thechild to an acceptable level of comfort.

SECONDARY INFECTIONS OF ATOPIC DERMATITISIf a child’s atopic dermatitis is very persistent and

doesn’t improve with appropriate treatments, look for infec-tion. Yeast can be a problem, and don’t forget to considereczema herpeticum. If a pediatric patient presents withlesions that don’t clear with antibiotic treatment, considera herpes simplex infection.

Also consider methicillin-resistant Staphylococcus aureus

(MRSA) in some atopic dermatitis patients. In Houston andChicago, places that had some of the earliest extensive expe-rience with community-acquired MRSA, problems with high col-onization rates of MRSA in atopic dermatitis patients havebeen noted. In the face of MRSA, people have been usingtwice-a-week bleach baths with nasal mupirocin to try to mini-mize the need for consistent use of systemic antibiotics.Good controlled trials using such therapy have yet to be pub-lished, but many centers are investigating the utility of bleachbaths to decrease the incidence of secondary infection in chil-dren with chronic skin conditions such as atopic dermatitis.

Dr. Friedlander is Clinical Professor, Pediatrics & Medicine at

Rady Children’s Hospital San Diego and UCSD School of

Medicine. Dr. Eichenfield is Professor of Pediatrics and

Medicine) and Chief, Pediatric and Adolescent Dermatology at

UCSD School of Medicine and Children’s Hospital in San Diego.

REFERENCES1. Haggstrom AN, Drolet BA, Baselga E, et al. Prospective study of infantilehemangiomas: clinical characteristics predicting complications and treat-ment. Pediatrics. 2006;118:882-887.2. Bennett ML, Fleischer AB Jr, Chamlin SL, Frieden IJ. Oral corticosteroiduse is effective for cutaneous hemangiomas: an evidence-based evalua-tion. Arch Dermatol. 2001;137:1208-1213.3. Enjolras O, Breviere GM, Roger G, et al. Vincristine treatment for func-tion — and life-threatening infantile hemangioma. Arch Pediatr.2004;11:99-107.4. Metry DW, Dowd CF, Barkovich AJ, Frieden IJ. The many faces of PHACEsyndrome. J Pediatr. 2001;139:117-123.5. Drolet BA, Dohil M, Golomb MR, et al. Early stroke and cerebral vascu-lopathy in children with facial hemangiomas and PHACE association.Pediatrics. 2006;117:959-964.6. Orlow Sj, Isakoff MS, Blei F. Increased risk of symptomatic hemangiomasof the airway in association with cutaneous hemangiomas in a “beard” dis-tribution. J Pediatr. 1997131:643-646.7. Metz BJ, Rubenstein MC, Levy ML, Metry DW. Response of ulcerated per-ineal hemangiomas of infancy to becaplermin gel, a recombinant humanplatelet-derived growth factor. Arch Dermatol. 2004;140:867-870.8. Kim HJ, Colombo M, Frieden IJ. Ulcerated hemangiomas: clinical charac-teristics and response to therapy. J Am Acad Dermatol. 2001;44:962-972.9. David LR, Malek MM, Argenta LC. Efficacy of pulse dye laser therapy forthe treatment of ulcerated haemangiomas: a review of 78 patients. Br JPlast Surg. 2003;56:317-327.10. Sugarman JL, Mauro TM, Frieden IJ. Treatment of an ulcerated heman-gioma with recombinant platelet-derived growth factor. Arch Dermatol.2002;138:314-316.11. Ritter MR, Dorrell MI, Edmonds J, Friedlander SF, Friedlander M. Insulin-like growth factor 2 and potential regulators of hemangioma growth andinvolution identified by large-scale expression analysis. Proc Natl Acad SciU S A. 2002;99:7455-7460.12. Friedlander SF, Ritter MR, Friedlander M. Recent progress in our under-standing of the pathogenesis of infantile hemangiomas. Lymphat Res Biol.2005;3:219-225.13. Barnés CM, Huang S, Kaipainen A, et al. Evidence by molecular profil-ing for a placental origin of infantile hemangioma. Proc Natl Acad Sci U S A.2005;102:19097-19102. 14. Frieden IJ, Haggstrom AN, Drolet BA, et al. Infantile hemangiomas: cur-rent knowledge, future directions. Proceedings of a research workshop oninfantile hemangiomas, April 7-9, 2005, Bethesda, Maryland, USA. PediatrDermatol. 2005;22:383-406.15. Lawry MA, Haneke E, Strobeck K, Martin S, Zimmer B, Romano PS.Methods for diagnosing onychomycosis: a comparative study and review ofthe literature. Arch Dermatol. 2000;136:1112-1116.16. Gupta AK, Skinner AR. Onychomycosis in children: a brief overview withtreatment strategies. Pediatr Dermatol. 2004;21:74-79.17. Aguilar C, Mueller KK. Reversible agranulocytosis associated with oralterbinafine in a pediatric patient. J Am Acad Dermatol. 2001;45:632-634.18. Williams ML, Pennella R. Melanoma, melanocytic nevi, and othermelanoma risk factors in children. J Pediatr. 1994;124:833-845.19. DeDavid M, Orlow SJ, Provost N, et al. Neurocutaneous melanosis: clini-cal features of large congenital melanocytic nevi in patients with manifest cen-tral nervous system melanosis. J Am Acad Dermatol. 1996;35:529-538.20. Rhodes AR, Albert LS, Weinstock MA. Congenital nevomelanocytic nevi:proportionate area expansion during infancy and early childhood. J Am AcadDermatol. 1996;34:51-62.21. Marghoob AA, Dusza S, Oliveria S, Halpern AC. Number of satellite nevias a correlate for neurocutaneous melanocytosis in patients with large con-genital melanocytic nevi. Arch Dermatol. 2004;140:171-175.22. Smith FJ, Irvine AD, Terron-Kwiatkowski A, et al. Loss-of-function muta-tions in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet.2006;38:337-342.23. Weidinger S, Novak N, Klopp N, et al. Lack of association between Toll-like receptor 2 and Toll-like receptor 4 polymorphisms and atopic eczema.J Allergy Clin Immunol. 2006;118:277-279.24. Allam JP, Bieber T, Novak N. Recent highlights in the pathophysiology ofatopic eczema. Int Arch Allergy Immunol. 2005;136:191-197.25. Paller A, Eichenfield LF, Leung DY, Stewart D, Appell M. A 12-week studyof tacrolimus ointment for the treatment of atopic dermatitis in pediatricpatients. J Am Acad Dermatol. 2001;44:S47-57.26. Meurer M, Folster-Holst R, Wozel G, et al. Pimecrolimus cream in thelong-term management of atopic dermatitis in adults: a six-month study.Dermatology. 2002;205:271-277.27. Wahn U, Bos JD, Goodfield M, et al. Efficacy and safety of pimecrolimuscream in the long-term management of atopic dermatitis in children.Pediatrics. 2002;110:e2.

S U P P L E M E N T T O S K I N & A G I N G • O C T O B E R 2 0 0 7 • 1 1

RETINOID THERAPY

Almost all acne patients should be on retinoid therapy.Although topical retinoids are also anti-inflammatory, their

major mechanism is to break up the comedo. One disadvan-tage to topical retinoids is they can be slow to start working, soalthough patients can improve with retinoid monotherapy, they’lllikely become non-compliant before they get better. When youstart retinoids, also start a topical antibiotic, and warn thepatient that although the retinoid may be irritating, it’s the mostimportant step. After about 12 weeks in patients who have hada big improvement with the oral antibiotic, you can stop theantibiotic and maintain them with retinoid therapy.

Also, don’t hesitate to use retinoids on patients withinflammatory acne. You just need to explain to the patientwhat side effects to expect. If you’re concerned a patientwill be too sensitive, alternate every other day between alow-concentration retinoid and a benzoyl peroxide for 2 weeks. Or, just have the patient use a benzoyl peroxidecleanser. Of your patients with fair, sensitive skin, 95% willtolerate the regimen. n

CHECK YOUR DIAGNOSIS

Apatient who does not have severe acne, but enoughacne to keep him or her coming back to a dermatologist

regularly and who has failed a number of treatment optionscan be very frustrating. If a patient is not getting better withthe diagnosis that you’ve made with the appropriate treat-ment for that diagnosis, re-evaluate the diagnosis. n

PRESENTED BY GUY WEBSTER, M.D., PH.D., LAWRENCE EICHENFIELD, M.D.,

AND ALAN SHALITA, M.D.

STRATEGIES IN ACNE AND ACNEROSACEA MANAGEMENTHIGHLIGHTS OF THE ACNE SYMPOSIUM AT ACMD 2007.


THE IMPORTANCE OF HORMONAL EVALUATION

In adult women with refractory acne, one of the most over-looked diagnostic tests is the hormonal evaluation. Even if

the hormonal evaluation is normal, treatment with hormonalmedications can be very helpful. Treatment with oral contra-ceptives, such as Yasmin and Yaz, or the androgen blockerspironolactone is a good step to take before trying isotretinoin.

However, it’s important to remember that it can take monthsto see the effects of oral contraceptives. When you inhibit thebinding of androgens to the sebaceous gland, it takes 2 or 3 months of therapy before that shows up as decreased pim-ples. Patients seem to respond quicker to spironolactone thanthey do to the other hormone blockers. n



ANTIBIOTIC AVOIDANCE

With long-term treatment of patients with stubborn acne,we need to avoid using antibiotics as much as possi-

ble. If the patient needs it, use it, but if we can develop tricksto get patients off antibiotics forever, like using retinoids andlimiting oral antibiotic treatment to 12 weeks in patients whohave had at least 75% improvement in their acne, we’ll bedoing our part as citizens in the “MRSA world” to keep animportant drug for treating MRSA active. n

IPLEDGE COMPLIANCE TIPS

Get blood labs done several days prior to patient visitsso that you’re sure the patients have them at their

appointments. Also, identify all isotretinoin patients andpull their labs before they visit the clinic. Be routine in theway you handle your isotretinoin patients. For example,have hand-outs for your isotretinoin patients. Use stan-dard forms for these patients, such as a standardisotretinoin follow-up note that is filled out at every visitand lists the start date of the medicine, the patient’sweight, the quantity of medicine by weight that the patientreceived per day, a line to indicate if symptoms/sideeffects were reviewed and a comments section. This formwill help focus the isotretinoin exam. This form shouldalso include the patient’s iPLEDGE number so that itbecomes part of the record. An isotretinoin symptom sur-vey is also a useful standard form. n

ISOTRETINOIN AND DIET

One of the most commonly ignored issues withisotretinoin is that the medication cannot be taken on

an empty stomach. If taken on an empty stomach, thepatient won’t absorb as much — it needs to be taken witha high-fat meal. n

COMPLIANCE

When treating acne, compliance is a big concern, par-ticularly when treating teenagers who have stubborn

acne. If a patient is not getting better with treatment,check if the patient is compliant. To help encourage com-pliance, try to minimize the complexity of the regimens.When it comes to acne care, assume that patients are notgetting all the medicine, especially when treatingteenagers. When trying to check if a patient is compliant,don’t ask what is his or her prescription. Ask questions inopen, non-judgmental ways. For example, if a patientshould be taking an oral prescription twice a day, so 14doses per week, ask the patient how many of the 14 doseshe or she takes on average per week. n


ISOTRETINOINAND PATIENT SOCIALHISTORY

It can be difficult to getpatients to be honest

about any changes intheir social histories. Itmay help to have apatient fill out a form inwriting or on a comput-er rather than askingthem in person. Eventhough they know thatyou are going to look atthe data, you get amore honest responsefrom someone doingthe data entry, inde-pendent of the directquestioning. After the form is completed, review it and focusquestions around the patient’s answers and record anyadditional information on the main sheet. n

WHEN ROSACEA TREATMENT FAILS

When patients with mild rosacea fail to respond to stan-dard treatment, consider that a second disease, such

as eczema or seborrheic dermatitis, may be the driving it.This is often the case with pediatric rosacea cases. In pedi-atric patients with suspected rosacea, one of the biggestmisdiagnoses is mistaking rosacea for what is really ker-atosis pilaris with lateral cheek erythema. Many patients’family doctors make this mistake. Keratosis pilaris does notrespond to rosacea medication at all. It sometimesresponds to pulsed-dye laser treatment, but not to any ofthe drugs used to treat rosacea. n

CHALLENGES TO ACNE LASER THERAPY

We still don’t know enough about the effectivenessof laser and light therapy for acne. All of the stud-

ies have been small and very few of them have lookedat light or laser treatment alone — most of the studiesoften combine the laser or light treatment with a topi-cal treatment, which makes it hard to know which treat-ment is effective. Because most of the studies done todate have not been funded by large companies, thenumber of patients recruited for individual studies hasbeen small. What results is that most outcomes areanecdotes from individual doctors, sample sizes aresmall and treatment regimens are greatly varied.

One of the challenges to laser and light therapies is thatthe targets of acne treatments are deep in the skin and sev-eral intervening structures exist. When treating the seba-ceous gland, you’re going through the non-sebaceous glandsand can damage them, creating the potential for scarring. n

THE UNDERLYING CAUSE OF ROSACEA

It is now believed that the primary underlying cause ofrosacea has nothing to do with Helicobacter pylori or what a

patient eats. Demodex may be an exacerbating factor, but notthe cause. We still don’t know for sure what causes rosacea,but it’s probably a disturbed control of inflammation — theinnate immune system bactericidal peptides may be prote-olytically cleaved into irritating compounds. Interestingly, thedrugs that make rosacea better are those that inhibit matrixmetalloproteinases (MMPs), such as doxycycline. n

Chemoprevention may be a bit of a misnomer — some ofit is therapeutic, some of it is prevention of problems andsome of it is about ancillary cosmetic benefits. We’ll dis-

cuss the various options of chemopreventative therapy.

IMIQUIMOD THERAPYApplication of imiquimod induces the local elaboration of a

kind of “cytokine soup.” A variety of materials are induced whenthis particular compound interacts with plasmacytoid and den-dritic cells, and also to some extent, with monocytes,macrophages and keratinocytes. All these compounds thenlead to various reactions such as chemotaxis and programmedcell death (apoptosis). Otherinduced compounds mayenhance enzymatic repair ofharmful UV-related geneticalterations in keratinocytes.

There are standard regi-mens for imiquimod (Aldara),but no two people are thesame. This is not a drug thatcan be put on autopilot —adjustments need to be made for individual patients.Patients are variably responsive, with a wide range of reac-tions to imiquimod application. You have to monitorpatients on imiquimod — preferably at 2-week intervals —and titration of dosing frequency and duration is dependentupon the patient’s response. Imiquimod is an immuneresponse modifier and all individuals have slightly differentimmune systems and therefore respond differently, so youhave to adjust it accordingly. It may seem like a lot of work,but it’s worth it in some situations. And in other situations,some of the other modalities, which will be discussed fur-ther in this article, may be better.

Genital Human Papillomavirus. Imiquimod was originallyapproved for genital human papillomavirus.1,2 The response

is different in men than in women. In men, somewherebetween 33% to 54% have clearing, while 72% to 100% ofwomen clear.1 If the lesion is not cleared, imiquimod treat-ment can be combined with a destructive modality.

Aside from the pivotal study, another non-U.S. study showedsimilar kinds of results.2 In this open-label study, treatmentwas administered three times a week for up to 16 weeks.More than half of all participants (103 of 191) were com-pletely clear. When 92 of the 103 patients who cleared werefollowed over an extended period of time, 15% or 16% hadrecurrences. When recurrence does occur, treatment can bere-administered the same way or combined with a destructive

technique. Patients rarelyhave a second recurrence.

One Australian study3 ofwomen showed there was nostatistical difference betweenusing imiquimod for a short-time period (4 weeks) versusa long-time period of 16weeks, as the drug is labeledfor use in the United States.

Molluscum Contagiosum. There are two clinical types ofmolluscum contagiosum — one affects adults and the otheraffects children. Adult molluscum is transmitted sexuallythrough direct skin-to-skin contact and affects the genitalia,suprapubic skin and upper inner thigh. In children, it spreadsthrough direct contact as well, and is typically on the face,trunk and upper extremities.

Adults respond better to treatment, and molluscum is treat-ed the same way genital warts are treated. Treatment is typi-cally three times a week for as long as it takes, which is rarely16 weeks, and typically 4 to 6 weeks, or possibly 8 weeks.

Treatment of pediatric patients is more difficult. A varietyof treatment options exist, and imiquimod, as an immuneup-regulator, has been suggested as beneficial for mollus-

BY TED ROSEN, M.D., MICHAEL H. GOLD, M.D., AND WM. PHILIP WERSCHLER, M.D., F.A.A.D., F.A.A.C.S.


CHEMOPREVENTIONITS ROLE IN DERMATOLOGY TREATMENTS.


Imiquimod is not a drug thatcan be put on autopilot —adjustments need to be

made for individual patients.

cum. An open-label, prospective study4 was conducted with12 patients aged 12 years or younger. Imiquimod wasapplied three times per week for up to 16 weeks. Threepatients withdrew — one developed flu-like syndrome andtwo had no effect. Of the remaining nine, seven cleared com-pletely, which is about a 60% clearance rate. It’s not 100%,but for a patient who has fields of molluscum, when curet-ting would be really inhumane and other modalities may notfeasible, it’s worth trying imiquimod.

A randomized study of 124 pediatric patients aged 1 yearto 18 years, compared curettage, cantharidin, salicylic/lacticacid combination and imiquimod as treatments for mollus-cum contagiosum.5 The results showed that patients favoredcurettage, saying it was the most effective and had lowpotential for adverse events, although you do have to controlthe bleeding and the treatment usually involves childrenscreaming while parents hold them down. Cantharidin,because of the blisters and the pain and the number of vis-its required for re-application to attain clearance, was rankedlower. Most of the children involved in the study didn’t like orwouldn’t tolerate the salicylic and lactic acid combination.

Study participants ranked imiquimod right behind curettageas a reasonable treatment, although it works slowly.Children do take longer than adults to respond to imiquimod— you may need the full 16 weeks of therapy for children,and the dose may need to be increased from three to five toseven times per week.

And, as with wart treatment, treatment modalities can becombined. In an open-label study of 16 children, a singleapplication of cantharidin, followed by imiquimod every nightfor 5 weeks, resulted in a totally clear or nearly clear rate.6

Actinic keratosis. The reason imiquimod is attractive is notfor the single actinic keratosis (AK) on the tip of the nose,but for patients who have an entire cosmetic unit or severaladjacent cosmetic units studded with AKs.

In a pivotal U.S. study of twice-weekly imiquimod treat-ment for AKs, 45.1% of patients had total clearing and59.1% had partial clearing (≥75% clearance).7 (See Table 1.)In a Phase III European study,8 when treatment wasincreased to three times per week, the numbers improved.More than half (57.1%) had total clearing and 72.1% hadpartial clearing (≥75% clearance). (See Table 2.)

Several meta-analyses have been completed comparingimiquimod to its closest kind of analogous therapy, which is5-fluorouracil (5-FU), and there’s overlap with complete clear-ance rates. Neither agent, when looking at clearance rates,is absolutely, inherently, predominantly superior. They bothwork, and there’s some overlap. One of these analyses triedto make a convoluted argument that imiquimod was better,but it really is so much of an overlap in any given patient thatwe can’t really say.9,10

The advantage of treating actinic keratoses withimiquimod is a durability of fix — a randomized, double-blind, placebo-controlled study showed that most patientswere still clear a year and a half after treatment, and thosewho weren’t clear typically had just a single AK.11 This kindlong follow-up data doesn’t exist for other modalities.

Part of what imiquimod does is up-regulate interleukin 12,which in the last year has been shown to enhance the set ofenzymes that is responsible for DNA repair. Why do we haveAKs? Because there is abnormal DNA that doesn’t allow thecells to control their multiplication.

A study in press12 compared imiquimod, 5-FU andcryosurgery. When looking at clinical clearance in this side-by-side study, the number-one modality was cryosurgery.Imiquimod and 5-FU were virtually identical and just slightlyless than cryosurgery. But, when the researchers went backand biopsied each lesion that was treated and looked at his-tologic clearance, imiquimod and 5-FU were much better thancryosurgery. When researchers looked at genetic abnormali-


Table 1. Phase III Imiquimod-AK U.S. Trials

TotalClearing

PartialClearing*

Imiquimodtwice weekly

n = 21545.1% 59.1%

Placebotwice weekly

n = 2153.2% 11.8%

*Partial Clearing means ≥75% clearance

Table 2. Phase III Imiquimod-AK European Trials

TotalClearing

PartialClearing*

Imiquimod3X weeklyn = 143

57.1% 72.1%

Placebo3X weeklyn = 143

2.2% 4.3%

*Partial Clearing means ≥75% clearance


ties, the mutations that lead to actinic keratosis, the muta-tions were no longer found in the imiquimod-treated areas,which explains the durability of fix. If you change the genet-ics, you don’t have the cells multiply, which is a major advan-tage of imiquimod.

Actinic Cheilitis. Imiquimod treatment for actinic cheilitiscan be painful, but it works. Patients need to applyimiquimod twice a day to the lips, 3 days per week, andattempt to complete 20 to 30 applications. Hemorrhagiccrusting usually results, followed by clearing with a highdegree of regularity.

Superficial Basal Cell Carcinoma. Imiquimod is approvedfor treatment of superficial basal cell carcinoma (sBCC).When imiquimod is applied five to seven times a week overthe course of 6 weeks, patients see an above 80% clinicalclearance rate, verified by his-tology.13 However, there arerecurrences. One open-label,long-term European study,14

found that following treat-ment five times a week for 6 weeks, 90% of superficialbasal cells were clear. Twoyears later, that 90% clear-ance rate became 80%.

Another open-label, long-term Australian study, foundthat 6 months after treat-ment, more than 94% wereclear.15 Two years later, that94% became 82%. Whileimiquimod is a useful modal-ity for sBCC, especially onareas like the chest and fore-leg where scarring is a big issue, you have to monitorpatients because they can develop recurrent lesions.

Nodular Basal Cell Carcinoma. Studies have shown thatthe histologic clearance of nodular basal cell carcinoma(nBCC) is insufficient to warrant imiquimod treatment.16

However, there may be a place in the treatment of nBCC forimiquimod as an adjunct. In one study, electrodesiccationand curettage were done three times, followed by applicationof placebo or imiquimod daily for 4 weeks.17 At 8 weeks, thesites were excised, and the areas where imiquimod wasused as post-standard therapy were less likely to have anyresidual BCC, as well as less scarring.

In another study, researchers looked at imiquimod as anadjunct to curettage with no desiccation.18 Post-curettage,imiquimod was applied every day for 6 weeks and the

majority of patients (31 of 34) had clinical and then veri-fied histologic clearing.

Studies have also found that imiquimod is an effectiveadjunctive therapy to Mohs surgery for nBCC. One studyshowed that pre-treatment with imiquimod for 6 weeks,resulted in reduced Mohs surgery defect relative to initialtumor size.19 In another study, imiquimod was used fivetimes per week for 6 weeks post-Mohs, and there was norecurrence for 20 to 34 months follow-up.20

Squamous Cell Carcinoma In Situ. More research is neededto show evidence of long-term clearance. Imiquimod for SCCin situ looks to have a high cure rate, but there have been sev-eral cases where invasive SCC has appeared in its place.

One study looked at treating SCC in situ with a combi-nation of imiquimod and 5-FU when inadequate response

occurs to either modalityby itself.21 Results showeda vigorous reaction, butthat it works.

Keloids. Imiquimod is pri-marily used for keloids onthe earlobes. One studylooked at imiquimod as anadjunct treatment to exci-sion of earlobe keloids.Imiquimod was appliedpost-excision for a 2-monthtime period, overnight, everynight, resulting in a reducedrecurrence of keloids with a92% success rate.22

Chemoprevention. Whenorgan transplant patientswho did not reject their

organs applied imiquimod three times per week and werefollowed for more than 1 year, they had fewer dysplasticlesions and/or warts that appeared.23-28

IMIQUIMOD: ADVERSE EVENTSImiquimod has potential side effects for which you need

to be aware. Psoriasis can worsen or be induced becauseimiquimod induces cytokines.29 Vitiligo may be induced intreated areas because imiquimod induces a cell-mediatedimmune response that can knock out the pigment cells.30

Imiquimod can worsen eczema.31 Imiquimod has actuallyflared sero-positive rheumatoid arthritis.32 And, in patientswhose genital warts are being treated and who also alreadyhave pre-existing benign prostatic hypertrophy, acute urinaryretention can occur.33


The advantage of treatingactinic keratoses with

imiquimod is a durability of fix— a randomized, double-

blind, placebo-controlled studyshowed that most patientswere still clear a year and a

half after treatment, andthose who weren’t clear

typically had just a single AK.11

Don’t use imiquimod on a patient who is unreliable or non-compliant. It is also not a good treatment for a patient whois highly risk-averse or who is known or suspected to be liti-gious. Also, it’s important to determine what you’re treatingbefore deciding to try imiquimod treatment.

5-FLUOROURACIL THERAPY AND AKSActinic keratosis is the second most common diagnosis

made by dermatologists, accounting for approximately 5 mil-lion visits in 2003.34 However,we know that most dermatolo-gists are managing AKs withsome type of surgical destruc-tion because despite thisbeing the second most com-monly diagnosed condition,there’s not a product used inthe management of AKs that’samong the top-20 drugs pre-scribed for dermatology condi-tions in the United States.35

Actinic keratoses are typically described as being pre-can-cerous or pre-malignant conditions, and there is some typeof a continuum of sun exposure, sun damage, a latent peri-od of proliferation of atypical clonal expansion of cells fol-lowed by the development of a pre-malignant lesion, whicheventuates into typically a squamous cell carcinoma. Weknow that both actinic keratoses and SCC share a p53 genemutation, and there are 200,000-plus cases of SCCs in thiscountry each year.36-41 So, when we treat actinic keratosis,we’re engaging in the prevention of skin cancer. And, if treat-ment is with a topical product (versus physical destruction),

then we’re engaging in chemoprevention, not just of thedevelopment of pre-cancerous lesions, but the chemopre-vention of skin cancer.

The optimal management plan for sun-damaged skinbegins with education to cover up, use sunscreen, avoidunnecessary sun exposure and stay out of tanning beds.Regular total-body self skin exams are vital, supplementedby total-body skin exams in the dermatology office at inter-vals appropriate to the patient’s history.

When treating visible lesions, the typical approach most of uswill use is physical destruction for removal. Liquid nitrogencryosurgery is safe, fast, effective, easy to perform, well toler-ated and usually requires only one treatment.42 It does hurt andit commonly leaves blisters, and it can leave those small areasof relative hypopigmentation on the background of actinicallybronzed skin, but it’s a very effective treatment.43

Electrodesiccation and curettage is also an option — it providestissue for biopsy that can be tested for malignancy, but it usu-ally leads to residual hypopigmentation and scarring. Otherdestructive modalities, such as chemical peeling, dermabra-sion, laser ablation (resurfacing) etc., may be effective in certainclinical situations; however, these treatments typically are notroutinely used for the average AK patient.

These options target visible lesions. You still need tothink about the management of the pre-clinical, latent orsub-clinical photodamaged skin, which is where topical 5-FU

comes into play. Topical 5-FU is FDA approved forthe treatment of AKlesions, it treats the entirearea, and treats multiplelesions. The disadvantagesinclude irritation associatedwith treatments, it requireslonger treatment durationthan destruction, it causessun sensitivity during use,and it can be expensive.

The American Academy of Dermatology guidelines ofcare support and encourage the use of combination ther-apy, such as cryosurgery and topical 5-FU. This combina-tion treatment is quick, easy, effective and cost-effec-tive.44 However, more randomized, controlled, long-termstudies are needed.

In one study looking at the use of 5-fluorouracil versusvehicle followed by cryosurgery, 6-month results showed bet-ter long-term management with combination therapy thanmonotherapy, which represents clearing of the subclinical orthe latent lesions. (See Table 3.)


Table 3. Mean Number of Facial AK Lesions

16

14

12

10

8

6

4

2

0

Mea

nLe

sion

Cou

nt

Baseline 4 Weeks 6 Months Baseline 4 Weeks 6 Months

Fluorouracil/Cryosurgery Vehicle/Cryosurgery

*p<0.001 vs. vehicle/cryosurgery group; *+p=0.011 vehicle/cryosurgery

4 weeks 6 months

13.7 13.1

4.3

9.1

4.46.2

The American Academy ofDermatology guidelines of care

encourage the use of combination therapy, such ascryosurgery and topical 5-FU.


Topical 5-FU has remarkable specificity against actinic ker-atoses.45 Acting as a “false base,” it interferes with DNA syn-thesis and influences RNA-directed activities.46 It’s a highly spe-cific and highly active molecule that has cytotoxic effects,which lead to the death of the pre-cancerous clonal expressionof these keratinocytes. Topical 5-FU also has the benefit ofhelping to improve the aesthetic appearance of the patient’sphotodamaged skin. Exactly how this occurs is debatable — itmay be part of the active chemotherapeutic process, or it maysimply be an inflammatory and exfoliative side effect.

As a treatment management option, 5-FU can be used as amonotherapy. It can be, and frequently is, used in combinationwith cryosurgery. Also, 5-FUcan be used with a topicalsteroid to minimize the inflam-matory effects. This has beenstudied, and does not appearto adversely affect the efficacyof 5-FU. It can also be used aspart of “interval therapy.”

Many dermatologists havetheir own set of protocolswhere they prescribe 5-FU onthe weekends, or for use twoor three times a week. It canalso be used as a sequentialor rotational therapy. Sincethere is no one treatment thatworks 100% for AKs, yourevolve and rotate throughone class of product to anoth-er, similar to standard chemotherapy for internal malignan-cies. For example, begin with freezing, then add the 5-FU reg-imen, then change to imiquimod, etc.

PATIENT COMPLIANCE STRATEGIES FOR 5-FUTypically, because there are several options for time and

frequency of treatment application, it’s possible to fit thistreatment into any patient’s schedule. For example, you canrecommend a 5% formulation twice a day for 2 to 4 weeks,or the 0.5% once a day for 1, 2 or 4 weeks. If a patient can-not tolerate 5-FU treatment for 2 or 4 weeks, have him or hertry it for 1 week. And, try combination treatment to minimizeirritation by using a topical mild- to moderate-potency steroidfor 1 to 2 weeks, usually once per day.

Again, 5-FU provides a blanket treatment or a “field-fire”like effect — it can safely and effectively cover a large area,but keep in mind that the new treatment paradigm for AKsthat’s emerging is one of combination and rotational thera-

py. Freeze, use a topical, rotate to another topical, seepatients back, and freeze again.

THE ROLE OF PDT IN CHEMOPREVENTIONThe preliminary data regarding photodynamic therapy’s

(PDT) role in chemoprevention are promising. Anecdotal datafrom clinical practice are also encouraging — we’re finding alonger duration before the development of new AKs and thedevelopment of non-melanoma skin cancers in patients whohave been treated with PDT.

Photodynamic therapy works when an active photosensi-tizer is put onto an area of actinically damaged cells and is

turned into PpIX — itbecomes activated when youuse a light source to destroysingle-cell oxygen. Althoughblue light and red light arethe main indicated sourcesfor PDT, a variety of differentlasers and light sourcesachieve an effect.

The two main photosensi-tizers being studied in derma-tology now are 20% 5-aminolevulinic acid (5-ALA)(Levulan) and methyl ester of20% 5-ALA (Metvix), which isFDA approved for the treat-ment of AKs and will be mar-keted in the United States forthat indication as Metvixia.

Levulan is FDA approved for 14- to 18-hour drug incubation forthe treatment of non-hyperkeratotic AKs on the face and scalputilizing a blue light for 16 minutes and 40 seconds.

Currently in the United States, this drug is used prima-rily to treat AKs, for photorejuvenation with or withoutAKs, acne, sebaceous gland hyperplasia and hidradenitissuppurativa. In Europe, though, it is mainly used for non-melanoma skin cancer and AKs. They are just beginningto study its use for photorejuvenation and acne. InAustralia and Europe, dermatologists use a red-light lasersource at 630 nm. It’s EU approval is for the treatment ofnon-hyperkeratotic AKs of the face and scalp and BCCsunsuitable for conventional therapy.

Chemoprevention may be the most important role for this ther-apy, and we’re just starting to get into what it can do and what ithas done. Initial clinical studies support the notion and morestudies need to be done to prove the concept, but the potentialfor PDT in chemoprevention is huge. (See Figures 1A and 1B.)


Again, 5-FU provides a blanket treatment or a

“field-fire” like effect — itcan safely and effectively

cover a large area, but keepin mind that the

new treatment paradigm for AKs that’s emerging

is one of combination and

rotational therapy.

A 2002 article in Cutis47 reviewed the treatment of severalpatients who had routinely developed two or three skin cancersper year. Patients were treated with individualized PDT treat-ments once or twice yearly, and this was effective for morethan 7 years. One patient developed only two skin cancers in9 years with once-yearly PDT treatments. Another patient whohad many different skin cancers, AKs, Bowen’s disease andSCCs, underwent four PDT treatments. This patient went about3 years without developing another skin cancer.

Another trial48 looked at the safety and efficacy of large-surface ALA-PDT and long-term application of ALA in hairlessmice. The researchers were able to show no evidence of for-mation of skin tumors with weekly blue light, ALA alone orALA-PDT for 10 months. Results showed that the effectappears to be a local effect. The same group also looked atthis with the methyl aminolevulinate49 and showed it didn’tcause skin cancers, as well.

Another group50 looked at several nevoid basal cell carci-noma cases, and other published case reports51 alsoshowed the incidence of development of new BCCs havebeen delayed with PDT treatment.

A December 2006 British Journal of Dermatology articlelooked at the Phase IV multicenter clinical trial with 12-month follow-up. This was a clinical trial using ALA withblue light showing that the incidence of new AKs was muchless than what would be expected.52

One article53 showed that PDT does not prevent cutaneousSCC. However, upon a more thorough examination of the

article, the number of AKs that you would expect to occurwas much lower, and the expected incidence of SCC was justabout the same as what they had found; therefore the over-all results showed that it was not efficacious. For AKs,though, it was shown to be effective.

One European study looked at immunosuppressed trans-plant patients and showed that the development of new AKswas delayed with the use of methyl ALA.54 This group pre-sented a multicenter ongoing trial with 20-month follow-uplooking at transplant patients who were treated with MAL-PDT or cryotherapy, and the number of AKs was lower inMAL-PDT areas compared to cryotherapy (p=0.009) at 3 months, with the data still the same at 20 months.

Mark Nestor, M.D., reviewed a subset of his population inFlorida with skin cancer.55 For 6 years, he followed a group ofpatients who had developed many skin cancers. After treat-ing the patients for 3 years with PDT, the number of skin can-cers that they developed was about one-quarter of what theywould have developed without PDT. There is a need for devel-opment of a large, multi-center study to evaluate PDT’s rolein chemoprevention in the United States.

ACITRETIN AND CHEMOPREVENTIONSeveral studies have shown that acitretin (Soriatane)

reduces the number of SCCs and decreases the formationof new lesions. Long-term therapy is needed, and it ismainly for organ transplant patients. You have to use long-term therapy, mainly in the organ transplantation popula-


Fig 1A & 1B. AKs before PDT and 3 years post PDT treatments. Photos courtesy of Dr. Michael Gold.

1A 1B


tion, those patients undergoing chemotherapy or thosepatients who are immunosuppressed. The highest-riskpopulation for developing cancers includes the organtransplant patient population, many of whom develop mul-tiple skin cancers. The implications for the transplant pop-ulation with this increased risk of non-melanoma skin can-cers and especially squamous cell carcinoma, is thepotential that these tumors are more aggressive withincreased morbidity and perhaps increased mortality, andan increased tumor burden.

One study56 looked at a case report of a 40-year-old malewho developed multiple SCCs after treatment with PUVA forsevere psoriasis. The patient received 25 mg/day ofacitretin for 25 months. The results showed the patient hadmore than 75% improvement in psoriasis and developed sixadditional SCCs (versus 14 SCCs pretreatment). Althoughhigher doses of oral retinoids may be more effective, lowerdoses may provide substantial reduction in development ofcutaneous malignancies.

Another study57 involved a 6-month trial of acitretin 30 mg/day vs. placebo in 44 renal transplant recipients.Results showed there was no deterioration in renal functionas well as a significant decrease (p=0.01) in the develop-ment of SCCs — 11% developed new SCCs in the acitretingroup versus 47% in the placebo group. Results showedtreatment was safe. Some patients experienced mild hairloss that was reversible upon discontinuation of acitretin.Other common side effects were dry lips and mouth. Relapseof SCC occurred when acitretin therapy discontinued.

A third trial58 was a randomized study of 26 renal transplantrecipients receiving different dosages of acitretin (0.4 mg/kg/day for 12 months versus 0.4 mg/kg/day for 3months followed by 0.2 mg/kg/day for 9 months). The resultsshowed a significant decrease (p=0.0001) in the number ofAKs (50% decrease) beyond 2 months in both groups.

In another trial,59 biopsies were taken in 33 renal transplantrecipients before and after 3 months of treatment with acitretintrying to prove that it alters the keratinocytes and that reduces theincidence of AKs both clinically and histologically. Results showedthat it reduced the epidermal thickness (p=0.002) and increasednormal differentiation parameter K10 (p=0.02). Safety showed nosignificant decrease in proliferation and dysplasia. Recurrence ofAKs was often seen after cessation of acitretin treatment, so forchemoprevention this needs to be a long-term therapy.

THE IMPORTANCE OF CHEMOPREVENTION FOR DERMATOLOGISTS

Both chemoprevention and chemotherapy of AK have asignificant and valuable place in our therapeutic armamen-

tarium. Chemoprevention is a very interesting topic whetheryou like imiquimod, 5-FU, PDT or acitretin, or any of the otherproducts. Dermatologists are the primary developers of thistype of patient care, and we need to understand these skinconditions well and be able to incorporate the various drugsinto our routine. Given the population demographics in theUnited States (aging of the Baby Boomers), we’re going tocontinue to see more and more patients with AK, so it’s upto us to take an active role not only in the management, butalso in the development of evidence-based managementprotocols utilizing combination therapy.

Dr. Rosen is Professor of Dermatology at Baylor College of

Medicine in Houston, TX. Dr. Werschler is Associate Clinical

Professor of Medicine and Dermatology at the University of

Washington, and Section Chief of Dermatology at Sacred

Heart Medical Center, Spokane, WA. Dr. Gold is Medical

Director of Gold Skin Care Center and Tennessee Clinical

Research Center in Nashville, TN. He is also Clinical Assistant

Professor in the Department of Medicine, Division of

Dermatology at Vanderbilt School of Medicine and School of

Nursing in Nashville, TN.

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29. Fanti PA, Dika E, Vaccari S, Miscial C, Varotti C. Generalized psoriasisinduced by topical treatment of actinic keratosis with imiquimod. Int JDermatol. 2006;45:1464-1465.

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36. Johnson TM, Rowe DE, Nelson BR, Swanson NA. Squamous cell carci-noma of the skin (excluding lip and oral mucosa). J Am Acad Dermatol.1992;26:467-484.

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40. Nelson MA, Einspahr JG, Alberts DS, et al. Analysis of the p53 gene inhuman precancerous actinic keratosis lesions and squamous cell cancers.Cancer Lett. 1994;85:23-29.

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43. Werschler P. Skin & Aging. 2002;9:S8-9.

44. Drake LA, Ceilley RI, Cornelison RL, Dobes WL, Dorner W, Goltz RW, GrahamGF, Lewis CW, Salasche SJ, Turner ML, et al. Guidelines of care for actinic ker-atoses. Committee on Guidelines of Care. J Am Acad Dermatol. 1995;32:95-98.

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47. Gold MH. The evolving role of aminolevulinic acid hydrochloride withphotodynamic therapy in photoaging. Cutis. 2002;69(6 Suppl):8-13.

48. Bissonette R, Bergeron A, Liu Y. Large surface photodynamic therapywith aminolevulinic acid: treatment of actinic keratoses and beyond. JDrugs Dermatol. 2004;3(1 Suppl):S26-31.

49. Caty V, Liu Y, Viau G, Bissonnette R. Multiple large surface photody-namic therapy sessions with topical methylaminolaevulinate in PTCH het-erozygous mice. Br J Dermatol. 2006;154:740-742.

50. Itkin A, Gilchrest BA. delta-Aminolevulinic acid and blue light photody-namic therapy for treatment of multiple basal cell carcinomas in twopatients with nevoid basal cell carcinoma syndrome. Dermatol Surg.2004;30:1054-1061.

51. Chapas AM, Gilchrest BA. Broad area photodynamic therapy for treat-ment of multiple basal cell carcinomas in a patient with nevoid basal cellcarcinoma syndrome. J Drugs Dermatol. 2006;5(2 Suppl):3-5.

52. Tschen EH, Wong DS, Pariser DM, et al. Photodynamic therapy usingaminolaevulinic acid for patients with nonhyperkeratotic actinic keratosesof the face and scalp: phase IV multicentre clinical trial with 12-month fol-low up. Br J Dermatol. 2006;155:1262-1269.

53. de Graaf YG, Kennedy C, Wolterbeek R, et al. Photodynamic therapydoes not prevent cutaneous squamous-cell carcinoma in organ-transplantrecipients: results of a randomized-controlled trial. J Invest Dermatol.2006;126:569-574.

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Mark Twain once said that wrinkles should reallyindicate where smiles have been. Unfortunately,wrinkles actually tend to represent more than just

smiles. There are many elements that add up to our per-ception of aging and/or wrinkling or photoaging. Manypatients present to dermatologists because they wouldlike to recapture some of what had been present in youth— perfectly symmetric lips that are plump and full, noaccentuation of the nasolabial fold, pristine skin and full,rounded cheeks. Basically, patients come to cosmetic der-matologists in search of a nice symmetric face.

Unfortunately, in 2007, we’re not quite able to achievethis perfect symmetry, nor should we be able to do so,but there are certainly waysand means to help patientsachieve a look that is a bitless wrinkled for an appro-priate age.

THE CONSEQUENCESOF AGING

Many changes actually hap-pen as we age that are naturalconsequences of aging. As weage, the epidermis thins andwe produce less turnover ofour skin. As a consequence,some of the protective mechanisms, like melanocytes andLangerhans cells, actually decrease in number and do not func-tion as well. As a result of these changes, we tend to see anincrease in skin infections, very fragile skin and a decreasedbarrier to the sun as well as decreased vitamin D production.The dermis also changes. We make less collagen and webreak down more elastin. These changes result in vascularfragility, pallor, impaired medication absorption, impairedwound healing and loss of elasticity and extensibility.

Beyond these typical effects of aging, photoaging canresult in epidermal hyperplasia, keratinocyte dyskerato-sis, variable melanosome distribution, and some inflam-mation of and thickening of the vessel wall. Also, somepatients who have an extensive amount of wrinkling andan extensive amount of dyspigmentation with the pres-ence of lentigines, may actually have a number ofbenign tumors and/or pre-cancerous or cancerouschanges to that skin.

FACTORS IN AGINGIn the last 5 years, one factor that has been shown to

play a significant role in aging is lack of estrogen. Asfemale patients age or stophormonal therapy, manycomplain of an aging look totheir skin. Estrogens help tokeep skin looking youthful interms of hydration of theskin and increased lipid pro-duction. A number of con-trolled studies have shownthat women who wereplaced on hormonal therapyeither with estrogen aloneor in conjunction with aprogestin or testosterone

showed a marked increase in skin collagen after time.Since there is a marked reduction in the use of hormonalreplacement therapy as a result of breast cancer con-cerns, there likely will be more lipoatrophy developing.

Patient wrinkling is markedly affected by the environmentbeyond sun exposure. Cigarette smoking, for example,causes vasal constriction and decreases the skin’s abilityto absorb products. There are many environmental ele-ments that also affect our aging, so we need to be cog-

BY SANDY TSAO, M.D., AND JOEL L. COHEN, M.D.


FACES AND FILLERSAN OVERVIEW AND A DISCUSSION OF POSSIBLE COMPLICATIONS AND TIPS ON AVOIDING THEM.


In the last 5 years, one factor that has been shownto play a significant role inaging is lack of estrogen.

nizant when patients present so that we can actuallyaddress those issues. If patients are undergoing treat-ments and spending time, effort and money on improve-ments, they need to be aware that they need to make asmany adjustments as possible in their daily lives in orderto preserve the changes we can make.

Lipoatrophy, which is a factor in the aging face, is basi-cally a loss of subcutaneous fat, and there are many rea-sons for development of this lipoatrophy, including impairedadipocyte differentiation and regulation, as well an upgradeof pro-inflammatory cells and cytokines that actually lead toa loss of actual fat. Without a deep appreciation for thisloss, you will not properly build or enhance the patient with the appropriate soft tissue augmenter.

Many conditions accentu-ate facial lipoatrophy. In par-ticular, HIV is one of thoseconditions. It’s very signifi-cant when a patient who hasHIV lipoatrophy also has avery extensive medicationlist. If you are going toadminister a filler to thatpatient, he or she has tounderstand that that a fillermay be longer lasting in apatient who does not haveHIV because some of themedications an HIV patientmay be taking will continueto break down the filler thatyou also place within the skin.

Cachexia is another condition that accentuates lipoatro-phy — many men and women who compete in enduranceexercises exhibit a lot of facial lipoatrophy. Diabetes, hered-itary syndromes and many autoimmune disorders also leadto facial lipoatrophy.

The major signs of facial aging are sallow skin with dys-pigmentation, gravitational changes, a loss of tissue elas-ticity and changes in intrinsic muscles or facial expres-sions. Many develop a glabella furrow, especially if they areconstantly frowning, reading or frequently smiling or raisingtheir foreheads. There may also be change of the musclesoverall — a wasting of the muscles over time. There is theloss of subcutaneous fat and, something we really cannotalter at the present, is remodeling of the underlying bone incartilaginous structures. So when you’re assessing exactlywhat is contributing to a patient’s facial aging, keep in mind

that there are many elements that contribute to thepatient’s condition. It’s not simply that he or she has anaccentuated nasolabial fold — you need to think about theunderlying reason why the patient has developed thesesigns of aging. By evaluating all possible causes, you willultimately create a treatment regimen that will provide thegreatest benefit for your patient.

TREATMENT OPTIONSMultiple therapy interventions are available. Sun

avoidance and sunscreen use are first-line protections.Retinoic acids, alpha hydroxy acids, exfoliative agents,hormone therapy and cosmetic interventions are all

useful treatments. When a patient presents

to your office, the mostcritical part of the evalua-tion is not the treatmentitself but the cosmetic con-sultation. Identify what thepatient envisions as theendpoint result to makesure that you can actuallyprovide it. Be sure thatyou’re in sync with thepatient as far as therisk/benefit ratio of all pro-cedures performed, as wellas the realistic results thepatient can expect. Thereis such a thing as toomuch treatment. Patients

want improvement but they don’t want to look likethey’ve been treated.

FILLERSThree elements make up the face — the upper, middle

and lower thirds of the face. When you alter one of the thirdsof the face, you are also affecting the other two-thirds, soyou need to make sure you balance treatment. Placement ofthe filler is key in addressing the total outcome. Fillers aremost often used in the middle and lower thirds of the face.

The optimal filler substance is easily administered,looks natural, is safe, stays in place, is predictable in itsoutcome, has minimal adverse side effects and is FDAapproved if it’s not autologous.

In general, fillers can be divided into two very basicgroups: biodegradable or semi-permanent, and non-biodegradable or permanent groups.


The major signs of facial aging are sallow

skin with dyspigmentation,gravitational changes,

a loss of tissue elasticity and changes in intrinsic muscles or

facial expressions.


When we use fillers, we’re trying to replace collagen aswell as some of the subcutaneous fat. We originally hadbovine collagens; now those have been replaced for themost part with human versions of collagen. They work for avery quick, easy fix and are ideal for a patient who has anevent to attend during the day and wants to have the leastpossibility of any bruising and/or redness. They are availableto be used right off the shelf without any allergy testing, butthese collagen fillers are short-lasting and expensive.

The hyaluronic acid fillers really revolutionized the way thatwe think about filler substances. The hyaluronic acid fillershave a very low allergy potential. The risk exists, but it’s low,so there’s no allergy testing, except for the fillers that arederived from animals.

Calcium hydroxylapatite (Radiesse) is not a hyaluronicacid; it’s actually calcium hydroxylapatite in a micropoly sac-charide gel. Once the vehicle is gone, you encourage neo-collagenesis to take place, which is why we get the long-last-ing benefits that we’re seeing with this product

Poly-L-lactic acid (Sculptra), a synthetic polymer that is bio-compatible, biodegradable, immunologically inert and freefrom toxicity, is another filler agent. It has a unique volumestimulating agent for induction of neocollagenesis. Multipletreatments are needed over a certain amount of time, butonce those treatments have been administered, results canlast from 1 to 1.5 years.

Autologous fat transfer is ideal when you need a filler thatwill provide a great amount of volume. It’s advantageous in

that it’s harvested from the patient and it’s easy to store. Itcan be frozen for about 1.5 years.

There are also more permanent fillers, such as Goretexstrips and silicone. Use these if you have a comfort level,but remember these are permanent.

COMPLICATIONS FROM FILLERSWe’re all going to see complications no matter what

fillers we choose to use. The important thing is to reallyunderstand what can go wrong and how to treat thesepost-procedure issues.

Injectors are not interchangeable. Injectable substancesare certainly not interchangeable either. There is just aboutevery level of sophistication available, from temporary tomore long-term fillers. Techniques differ between the waypeople use products. There are serial puncture and linearthreading techniques and then the more fanning and cross-hatching techniques; and, often, experienced injectors use acombination of these techniques depending on the locationof placement and the goal.

Understanding anatomy and where to place the filler isvery important. It’s also important to understand the prod-ucts, how we place these specific products, and be aware ofthe slight aesthetic differences that may change over time inwhat’s fashionable in terms of volume or geographic per-ceptions (Los Angeles vs. Denver vs. New York City).

To avoid superficial placement of fillers in the infra-orbitalarea, for example, we have to really understand the anatomy


Figures 1A & 1B. The patient’s undereye area pictured above left showed the discolored lump left by another practitionerwho poorly placed a hyaluronic acid filler. Above right, the patient’s problem was resolved with injection of hyaluronidase.Photos courtesy of Dr. Joel Cohen, M.D.

1A 1B

of this area. In our opinion, the use of botulinum toxin in thisarea has helped many of us get a sense of the nuances ofthis anatomic area, particularly the subcutaneous planesthat are involved and the way in which muscles function. Inparticular, threading the product below the orbicularis oculimuscle usually enables experienced injectors to avoid dis-crete bumps of filler material in this area. Injecting slowlyand uniformly also usually helps avoid placement of exces-sive volume and avoid significant bruising. With productssuch as Restylane and JuveDerm Ultra, use of a 32-gaugeneedle can be very helpful in small aliquot precise place-ment, as well as in slowing the overall injection process.

If nodules of product are visible, appropriate therapies forsuperficial placement includewaiting for the product to goaway, expressing the product,and very occasionally placingCosmoderm (which is opaque)over the area if the essentialproblem is a Tyndall effect of ahyaluronic acid filler ratherthan a really pronouncednodularity. For hyaluronic acidnodules, you can also usehyaluronidase enzyme, an off-label use of an FDA-approvedproduct, to dissolve it.

The January 2007 issue ofSkin & Aging included a write-up of an experience treating apatient with a very pronounced infra-orbital nodule after shereceived Restylane from another physician.1 Treatment witha Q-switched 1064-nm Nd:YAG laser may also be effective inreducing nodularities of some filler products.2

When Radiesse was first available, several physiciansused it in the lips, which led to several cases of whitish “pop-corn-like” nodules later occurring. This may have been due tosuperficial placement of the product, but also likely was relat-ed to the dynamic action of the orbicularis oris musclemechanically pumping the product superiorly toward the thinmucosa. Most physicians at this point avoid placingRadiesse specifically into the lips for this reason. If a patientdoes experience superficial whitish nodules from this productin any area, correction involves opening the area and express-ing the product (usually with an 18 g needle or an 11-blade).

With Sculptra (NewFill in Europe) there has been a higherincidence than we’ve seen in the United States of subcuta-neous papules or nodules. Also from Europe, there was a casereport in the July 2005 issue of Dermatologic Surgery of atroph-ic hypopigmented permanent scars after use of poly-L-lactic

acid.3 But, it is important to keep in mind that the originalEuropean experience with this product was usually associatedwith low-volume dilutions (often 2 cc to 3 cc), short reconstitu-tion times (often only a few hours) as well as superficial place-ment into the deep dermis. Using higher-volume reconstitutions(5 cc to 8 cc per bottle), longer reconstitution time (at leastovernight) and injecting deeper (into the subcutaneous fat) canmany times help prevent these types of potential complications.In addition, I think it is important to recommend that injectorsavoid trying to re-suspend the precipitate at the end of using aSculptra bottle, as this could potentially lead to too-concentrat-ed a product being injected. Also, it is essential to know whereyour needle tip is located, especially when using longer needles

(greater than 5/8 inch). Longerneedles more easily allowbending as well as extensionto adjacent cosmetic subunits,such that injections intendedin the superior cheek couldlead to superficial placementin the adjacent thin-skin of theinfra-orbital region. A recentreport reviews treatmentoptions for Sculptra nodules inthis infra-orbital region.4

Other very rare potentialproblems that may beencountered with the use of

filler substances include infections. Ensuring that you areusing an FDA-approved product acquired directly from theU.S. distributor is of paramount importance. There havebeen cases of injectors using unlicensed or counterfeitproducts that led to infections in some patients.5 In thesecases, several patients received an unlicensed hyaluronicacid product (Hyacel) by a woman posing as a physician ina New York City hotel room.

Obviously, infections can also potentially occur usinglicensed products by experienced physicians, as well.Sometimes it can be difficult to distinguish a sterileabscess versus a true infection, and we direct readers toa review of a protocol for these issues.6 To help avoid infec-tion, prep the skin — using alcohol or an agent likechlorhexidine — in the area of treatment prior to fillerplacement. If you suspect infection, culture the exudateand initiate treatment with an antibiotic such as clar-ithromycin until the more specific culture results becomeavailable. Of note, in the infra-orbital area, avoid chlorhexi-dine due to the potential of contact with the eye, whichcould result in formation of a keratitis.


With products such asRestylane and JuveDerm,use of a 32-gauge needle

can be very helpful in smallaliquot precise placement,as well as in slowing theoverall injection process.


Necrosis is a very serious potential side effect. If you injectinto a blood vessel, you’re going to have a problem. If you placetoo much product and thus too much pressure around theblood vessel, you’re going to have a problem. When treating theglabellar area, this risk is of necrosis is of particular concern.The glabellar area is perfused by small watershed arteriolesextending from the supratrochlear arteries, and product placedeither within a vessel or excessively around a vessel in thiscould lead to an immediate blanch and subsequent necrosisand slough of skin in the area. It is best to inject small volumesin this area, and to inject very superficially while monitoring theskin for any indication of a visible blanche.

CosmoDerm can be placed very superficially. In addition,hyaluronic acid products,such as Restylane andJuveDerm, are also commonlyused in this area. A reviewdelineating a protocol for thetreatment of necrosis waspublished last year.7 Also, twocase reports were publishedof treating impending necro-sis after use of a hyaluronicacid filler by the injectingphysician through use ofhyaluronidase enzyme.8,9

SENSITIVITYPersistent erythema often with swelling is a sign of

potential sensitivity in an area of previous treatment with afiller product. Fortunately, with newer filler products, thisissue is far less common than with previous experienceswith bovine collagen products, such as Zyderm and Zyplast.Hyaluronic acid products, such as Restylane and JuveDerm,have demonstrated very little sensitivity issues over time.Keep in mind that these sensitivity reactions can be animmediate or delayed phenomenon.

As far as immediate reactions, there was one report of apatient who had been treated with Botox and Restylane onthe same day alone with a lidocaine block. Within an hour,the patient experienced an angioedema reaction thatresponded to intra-muscular and then oral steroids.10 Withthe extremely rare potential of a product inducing anaphy-laxis, I think it is important to have a protocol in your officeand have an epinephrine pen on hand. Delayed filler sensi-tivities have been the more frequently described issues,particularly with bovine collagen. If there is an indication of apersistent sensitivity reaction, possible treatments includeintralesional steroid injections (ranging from 10 to 40 mg/cc of

triamcinolone), pulsed-dye laser treatments, hyaluronidase (inthe case of a hyaluronic acid filler being used) and rare reportsof efficacy of cyclosporine or imiquimod.

UNDERSTANDING POTENTIAL PROBLEMSIn short, it is important to understand what can go wrong with

the use of filler substances so that we can best learn either toavoid these problems or at least effectively treat them.Superficial placement, infection, necrosis and sensitivity aresome of these potential issues that we need to keep in mind.

Dr.Tsao is a Professor at Harvard University Medical School and

Clinical Director of

Massachusetts General

Hospital Laser Center.

Dr. Cohen is Director of

AboutSkin Dermatology and

DermSurgery in Englewood,

CO. He is Past President of

the Colorado Dermatologic

Society, Chair of the ASDS

Patient Education Committee,

and on the Board of Directors

of the American Society of

Cosmetic Dermatology and

Aesthetic Surgery.

REFERENCES1. Hirsch RJ, Cohen JL. Surgical insights: challenge: correcting superficial-ly placed hyaluronic acid. Skin & Aging. 2007;15(1):36–38.

2. Hirsch RJ, Narurkar V, Carruthers J. Management of injected hyaluronicacid induced tyndall effects. Lasers Surg Med. 2006;38:202-204.

3. Beljaards RC, de Roos KP, Bruins FG. NewFill for skin augmentation: anew filler or failure? Dermatol Surg. 2005;31:772-776.

4. Stewart DB, Morganroth GS, Mooney MA, et al. Management of visiblegranulomas following periorbital injection of poly-L-lactic Acid. Ophthal PlastReconstr Surg. 2007;23:298-301.

5. Toy BR, Frank PJ. Outbreak of Mycobacterium abscessus infection aftersoft tissue augmentation. Dermatol Surg. 2003;29:971-973.

6. Narins RS, Jewell M, Rubin M, Cohen J, Strobos J. Clinical conference:management of rare events following dermal fillers--focal necrosis andangry red bumps. Dermatol Surg. 2006;32:426-434.

7. Glaich AS, Cohen JL, Goldberg LH. Injection necrosis of the glabella: pro-tocol for prevention and treatment after use of dermal fillers. DermatolSurg. 2006;32:276-281.

8. Hirsch RJ, Cohen JL, Carruthers JD. Successful management of anunusual presentation of impending necrosis following a hyaluronic acidinjection embolus and a proposed algorithm for management withhyaluronidase. Dermatol Surg. 2007;33:357-360.

9. Hirsch RJ, Lupo M, Cohen JL, Duffy D. Delayed presentation of impend-ing necrosis following soft tissue augmentation with hyaluronic acid andsuccessful management with hyaluronidase. J Drugs Dermatol.2007;6:325-328.

10. Leonhardt JM, Lawrence N, Narins RS. Angioedema acute hypersensitiv-ity reaction to injectable hyaluronic acid. Dermatol Surg 2005;31:577-579.


If you suspect infection,culture the exudate and

initiate treatment with anantibiotic such as

clarithromycin until the more specific culture

results become available.

Several choices are available for both nonablative reju-venation and ablative laser surfacing. Typically, withnonablative rejuvenation multiple treatments are nec-

essary and there is minimum downtime, but the results aremild and patients often want more improvement. With abla-tive resurfacing, patients see great results and excellenttightening and sculpting, complete removal of epidermallesions and new collagen formation for at least 6 months, butablative procedures meanmore downtime and morerisks. Patients want a middleground — better results thanthey are seeing with nonabla-tive rejuvenation, but lessdowntime and less risk thanablative resurfacing.

THE MIDDLE GROUNDOPTIONS

Plasmakinetic Rejuvenation.

We can achieve excellentresults with plasmakinetic reju-venation (PSR). The results arenot as good as those seen withablative CO2 or multi-passerbium, but you can get tighten-ing with two passes. Results aresimilar to what we see with achemical peel, with the addedadvantage of thermally-inducedcollagen remodeling and contin-ued improvement for 6 to 12 months. To achieve these kinds ofresults, PSR treatment needs to be aggressive (3 to 4 joules).Downtime and risks are lower than with ablative options.

Patients better tolerate the downtime associated with PSRthan downtime from ablative procedures. They may want to

hide for a week, but they can go out. The epidermis stays inplace and acts as a dressing, so patients are more com-fortable and need less pain medications. Post-treatment,patients tend to look the worst when the epidermis sloughson days 4 through 7. In terms of risks, patients have lesserythema that clears sooner than with ablative resurfacing.There is milder hyperpigmentation and so far no permanenthypopigmentation or scarring has been noted.

If you are looking to achieve amore aggressive result,one goodcombination option includesdoing C02 around the eyes andaround the mouth and PSR onthe cheeks and the forehead.

Fraxel. The 1550-nm erbiumlaser produces microthermalzones about 100 to 300microns deep. Healing occursthrough lateral re-epithelializa-tion. Minimal aftercare is need-ed — typically just ice andhydration as needed forswelling. Patients don’t need todo soaks like they have to dowith ablative resurfacing.Unlike, even with plasma, thereis no epidermal sloughing. AfterFraxel, patients typically experi-ence swelling and a reddish-brown bronzing of their skin.

In terms of energy levels,use higher energy on the face than on the neck or chest.Starting energies for the face should be 9 mJ to 12 mJ,and 6 mJ to 10 mJ for the neck or chest. The microther-mal zone pass should be in the range of 125 to 250microns for 8 to 16 passes, usually 2000 MTZ/em2 total

BY SUZANNE L. KILMER, M.D.

THE MIDDLE GROUNDTHE OPTIONS BETWEEN ABLATIVE AND NONABLATIVE LASER THERAPY.


With ablative resurfacing,patients see great

results and excellenttightening and sculpting,

complete removal of epidermal lesions andnew collagen formationfor at least 6 months,

but ablative proceduresmean more downtime

and more risks.


density. The new Fraxel II starts with higher energies andhas levels that increase with increasing densities. Thetotal kJ depends on area size and location of what’sbeing treated (face: 5 kJ to 8 kJ; neck: 3 kJ to 4 kJ;hands: 1 kJ to 2 kJ).

When treating superficial lesions (melasma or epidermalpigment), the treatment protocol should be lower energiesand a higher number of passes if you’re using the Fraxel I.With the Fraxel II, start with 20 mJ at level 5 or 6. Whentreating deeper lesions (acne scars and rhytids), use ahigher energy to penetrate deeper, but use fewer passes.If you are using the Fraxel II, start with 35 mJ to 40 mJ atlevel 6 or 7. These parameters may need to be lowered ifyou are treating a patient with dark skin. Post-treatment,patients may experience some swelling and erythema for afew days, but significant improvement can be seen about2 months after treatment.

EFFECTIVE OPTIONSThe most improvement is clearly seen after treatment

with the CO2 erbium laser, but this significant improve-ment comes with significant downtime and risk; PSR andFraxel are much better tolerated. There is more down-time with these procedures than with nonablative reju-venation techniques, but less than the ablative alterna-tives. There are some patients, for instance those withsignificant sun damage and heavy folds who will needCO2 laser treatment, but there are many patients in themiddle who have some sun damage and wrinkling for

whom PSR and Fraxel will work. They would need multi-ple treatments with a Fraxel or they might prefer a singletreatment with PSR with a little bit more downtime withthat more aggressive treatment, but then get similarimprovement. These are both good options becausethey’re effective and the risk is much less than that seenwith the ablative treatments.

Dr. Kilmer is the Founding Director of the Laser & Skin

Surgery Center of Northern California.


Fig 1A & 1B. Figure 1a: Pre-PSR treatment and 1 month post-PSR treatment.

1A 1B

Fig 2A & 2B. Pre-Fraxel treatment and 1 month post-Fraxeltreatment.

2A 2B

The preface to the Code of Ethics reads, “Ethics arestandards of conduct, the essentials of honorablebehavior for physicians.” This sounds simple, but the

further you read, you find that ethics include moral principlesand matters of social policy.

The canons say that the physician owes a duty first to thepatient, second to society, thirdly to other healthcareproviders, and only fourth to the physician, him or her self.While the Code of Ethicsnever says this, the founda-tion that underlies medicalethics is a fiduciary relation-ship. A physician has a fiduci-ary relationship to his or herpatients. A fiduciary relation-ship says: The fiduciary, inthis case the physician, willalways place the interest ofthe beneficiary, in this casethe patient, ahead of his orher own interest. When facedwith an ethical dilemma, ask: “Does this action place thepatient’s interest ahead of my own?” If the answer to thatquestion is “yes,” then most likely, it’s the ethical way to act.

However, if there is a question at all, you may be engagedin unethical behavior. According to the code, the result ofprofessional conduct that fails to comply with the Code ofEthics, is censorship, suspension or possible expulsionfrom the medical society to which you belong. While thiswas considered a serious threat 80 years ago or so, todaythis threat does not hold much weight since a majority ofphysicians no longer belong to the American MedicalAssociation, and many physicians don’t even belong to spe-cialty societies. This is a problem and is one of the areaswhere medical ethics has been led astray, not so much byphysicians but by courts and medical boards.

The consequences of unethical practice in medicine, though,can be much more severe than the censorship, suspension orexpulsion deemed appropriate punishment by the Code of Ethics.

ETHICS AND THE LAWWhile the law and ethics are closely related, they clearly are

not the same. In some cases, ethical duties may exceed thelegal requirements. For example, if you have a patient who can-

not afford to pay you for yourservices, you are nonethelessethically bound to provide careto that patient. That is clearlyfar beyond what the lawrequires, which can make thisa difficult situation. The lawsays you may not waive a co-pay or a deductible, at leastfor Medicare patients; that isclearly a criminal act. For man-aged care patients, it isalmost certainly a breach of

your contract with the managed care companies to waive theco-pay. In that case, the ethical requirement is in opposition tothe legal requirement. So how do you choose which you’regoing to obey — the legal requirement or the ethical require-ment? This needs careful consideration.

In another instance, a three-doctor group had several inter-nal problems among the physicians, mostly dealing with com-pensation — who got paid how much, who paid what overhead,who did what work, how much work each was doing, etc. Thegroup hired me to help resolve their issues. One of the doctorsadmitted that the group, in fact, took cash off the table andnever reported it to the IRS in volumes that clearly amountedto a felony. The same physician also admitted that the groupupcoded their services by performing additional elements ofexaminations that gave them a higher level of service than was

BY GEOFFREY ANDERS, J.D., C.P.A., C.H.B.C.

ETHICS IN MEDICINEWHAT YOU NEED TO KNOW IN DAY-TO-DAY PRACTICE.


While the law and ethics are closely related, they clearly are not the same. In some cases, ethical duties may exceed the

legal requirements.


really medically justified. In a separate discussion about ideasto increase revenue for the practice, I suggested that the groupconsider dispensing generic drugs to the patients in the prac-tice. That physician responded, “I can’t do that. That wouldgive me a conflict of interest.” This physician had a problemwith proportion. Stealing money and not reporting it to the IRSis a felony. Upcoding is a felony. Both of these are crimes thatresult in criminal punishment. Yet, this doctor would notengage in what he perceived to be a conflict of interest by dis-pensing generic drugs. You need to have a sense of proportionand weigh the legal requirements versus ethical requirementsand the consequences of each.

That, unfortunately, is easier said that done. You areheld accountable to behave ethically. But to whose stan-dards are you held? The AMA has one set of standards,but individual specialty societies have their own ethicalrequirements. Also, even if you decided that the AMAcode is the one you should follow, it’s not always clearwhich behaviors are mandatory and which are recom-mended. For example, some statements say the physicianhas a duty to, but other standards say a physician shouldor a physician should not, and there are other statementsthat say the code strongly discourages a certain activity.Then in still other places it’s not a duty, it’s not a recom-mendation, it’s a guideline. This is a real problem.

Two things exasperate this problem. One is the rate ofchange in society. Society’s expectations change very rapidly.Ethics, on the other hand, change slowly because you need aconvocation of physicians to all agree on an ethical point tochange the rules. Therefore, the rules don’t always comport withwhat modern society expects. On top of that, you have judges— medical boards — that go far beyond what the canon ofethics say in terms of enforcing the code of ethics. In Alaska, ifyou behave unethically, you can lose your license. InMassachusetts, certain unethical behaviors have been labeledas gross misconduct, the result of which is loss of license. InPennsylvania, they have defined what is unprofessional con-duct, and say as long as you don’t engage in unprofessionalconduct, you’re o.k. You can be unethical and they can kick youout of the medical society, but at least you won’t lose yourlicense and you know where you stand. In Illinois, the courtshave said the patients have a right to rely on physicians behav-ing in accord with the ethical standards, which is disastrous.This means that if you don’t engage in ethical behavior, a patientcan sue you because they have a right to rely on your behavingethically. In Tennessee, about 2 years ago the TennesseeSupreme Court ruled that restrictive covenants are unenforce-able against physicians when employed by other physicians.This decision was based on the fact that the AMA code of ethics

says that restrictive covenants are strongly discouraged.Medical boards and judges will take these medical ethics andapply them in all sorts of ways that you can never expect.

It’s important to keep medical ethics in a sense of pro-portion with your other requirements in society, and do findout where your state stands in terms of the weight that isaccorded to medical ethics. Also, if the courts have notgiven a pronouncement on a specific issue in medicalethics, be very careful, tread very lightly before you takethat step into unethical behaviors.

There are many specific behaviors in which you engage ina day-to-day practice that you need to be aware of what isand is not ethical in regard to those behaviors.

ETHICS AND ADVERTISINGAdvertising is actually subject to no greater ethical

restraints than the law applies — advertising cannot bedeceptive, it cannot create unjustified medical expectationsand it has to be relatively clear. There are two kinds of adver-tising that are considered potentially or likely to be deceptive.

The first type is testimonial advertising, such as wherethe patient says, “I received wonderful care from Dr. Jones,”and the implication is that all patients will receive wonderfulcare from Dr. Jones.

The second type is advertising that implies certain results.For example, is advertising claiming, “The vast majority of


patients treated at XYZ Dermatology were extremely pleasedwith results of their care,” implying that any patient who comesto XYZ Dermatology will experience that particular result. Is itbetter to advertise that, “Ninety-five percent of the patients ofXYZ Dermatology were extremely pleased with the results oftheir care based upon patient surveys, which we have con-ducted”? This is probably more ethical because there are factsto back up the claim. Would it be different if the advertisementsaid, “Six months after receiv-ing care at XYZ Dermatology,95% of patients, as evidencedby patient surveys, decidedthat they were extremelypleased with the results oftheir care”? Again, this is prob-ably a more ethical way tostate this claim.

Or, if an advertisement forfacelifts shows a before-and-after picture, does it imply acertain result? From apatient confidentiality stand-point, does the ad breach confidentiality? For HIPPA purpos-es, did the doctor obtain specific authorization to use thispatient’s information for marketing above and beyond thenormal privacy notice?

In America each day, consumers are bombarded by approxi-mately 36,000 messages a day. Consumers in America tendto be fairly sophisticated. Does that have an impact on whetherthis before and after presentation is ethical or unethical? Dothe customers, the patients, understand that this is onepatient and they may not get the same result? Deciding ifsomething is ethical is not always black and white.

PATIENT COMMUNICATION AND ETHICSFrom an ethical standpoint, the code says that electronic

mail can be a very useful tool in communicating with patients.But, to use it, you must apprise the patient of the inherent lim-itations involved with e-mail. You may not use e-mail to estab-lish the initial physician-patient relationship. E-mail communi-cations should only be used to supplement in-person visita-tions or communications. The limitations that you need toapprise the patients of include letting them know about thepotential breach of privacy or breach of confidentiality becauseit’s possible for someone to hack into your e-mail. Also, youcan’t be sure with whom you’re communicating — if youreceive an e-mail from [email protected] claiming to be yourpatient, there’s no way to be 100% sure that it is really yourpatient. Somebody could have hijacked that user name.

There are also issues with possible delays in responses.For example, a patient may e-mail you about a rash he or shebelieves is very serious, but you’re at a conference or onvacation and not checking e-mail regularly. You may notrespond to that e-mail for days or weeks, and that can be aproblem. So you have to alert patients, preferably in person,to these inherent limitations before you can proceed withelectronic communications. And the code states that dis-

claimers reciting those prob-lems on your Web site or onyour return e-mail are not suf-ficient. You have to discussthese limitations with thepatients to be sure that theyhave a satisfactory under-standing of the limitations.

Beyond e-mail, Web sitesare required to have timely,accurate, reliable and scien-tifically sound information.The Web site is supposed tominimize the commercial

bias in conflict of interest if you are selling commercialproducts. There are supposed to be no recommendationsof unnecessary services. The code states, “Physiciansshall not provide, prescribe, or seek compensation formedical services that they know are unnecessary.” ThisWeb site stricture says you won’t recommend unnecessaryservices — not just unnecessary medical services but anyunnecessary services. But when you’re dealing with cos-metic dermatology, this can be difficult. For instance, whenwould a chemical peel be considered a necessary service?So does this mean that you cannot advertise chemicalpeels or other elective procedures on your Web site? Astrict reading would argue for that, but it’s difficult tobelieve that’s what is actually intended by this portion ofthe code. Again, though, this is the problem with thisgeneric AMA code of ethics when you’re discussing a spe-cialty like dermatology. The broad ethical requirementsmay not actually fit how the specialty has developed.

In regard to patient confidentiality, the biggest problemsoccur when a physician is communicating on an unautho-rized basis to someone other than the patient. For example,you may be one physician treating a patient who is nowsuing Dr. B. Say that Dr. B’s attorney, the defense counsel,calls and asks for your opinion on what has gone on withthis patient, and you talk to the lawyer. That is completelywrong. You may not discuss confidential information withanybody who is not explicitly authorized by the patient.


…advertising cannot be deceptive, it cannot

create unjustified medicalexpectations and it has

to be relatively clear.


Also, you may not disclose patient information to insurance companies unless the patient has author-ized it. Patient registration forms must include a state-ment saying, “You authorize us to disclose your medicalrecords to your insurance company.” Without that, youcan’t talk to the insurance company.

Of course, there are some things that you must discloseand that you do not need patient authorization to disclose.Suspected child or spousalabuse in all states isrequired to be reported tothe appropriate authorities.Interestingly, elder abuse istypically not included inthose statutes, but I expectthat as time goes by it willalso be required to bereported. Sexually transmit-ted diseases as required bystate law, have to be report-ed, and gunshot woundsalso have to be reported.

Communication regarding a patient who is a minor is slight-ly different. If you have a new patient who is a minor, you donot have to provide care without a parent’s consent. However,once you have a physician-patient relationship with that minor,then different rules come into play. You have the duty to pro-mote autonomy of the minor in decision-making with respectto care. You have the duty to encourage parental participation,but if the minor says “no,” then you may not communicatewith the parents or guardians. If a parent and a minor, a 15-year-old patient, come in for an appointment and the parentaccompanies the minor when the nurse or assistant comes totake the patient to the exam room, you have a duty to stopthat parent because you don’t know that the minor has con-sented to the parent’s participation in that episode of care. Tryto see the minor without the parent until you know that theparent’s participation in the episode is welcome.

A competent minor may consent to care and the physicianmay not inform the parent without the minor patient’s con-sent. This is true from a legal standpoint as well. Peopleunder the age of majority may contract for the necessariesof life and be legally bound by that contract. Medical care isa legal necessity and so the minor is responsible for the feeif he or she utilizes your services.

The Code of Ethics makes a distinction between confi-dentiality and privacy, though it seems to be a differencewithout a distinction. Confidentiality is information that isimparted to you in confidence, and something you clearly

cannot reveal. But the code goes on to say that you alsomay not disclose matters that you learn are private, eventhough they may not be confidential.

FEES AND ETHICSThere are many issues of ethics that relate one way or

another to fees. The first is fee-splitting, and this is themost traditional restriction. The narrow definition of fee-

splitting is a payment by orto a physician in exchangefor a referral. And that isclearly unethical. It is alsoillegal in many states. Thelegal definition is muchbroader than this traditionalethical definition. In NewYork, where an internistentered into a commerciallease that provided that thelandlord receive a monthlyrent, which consisted of aflat rental plus 5% of the

gross revenues of the practice, this was considered, appro-priately, illegal fee-splitting because it gave a non-doctor aninterest in the physician’s fees. There are instances whenit’s not as clear if a behavior is considered fee-splitting,though. For example, if a group practice of four dermatolo-gists divides income equally even if somebody is doingmore work than the other, so there is fee-splitting, that iso.k. Surgical assistant fees are a fee-split, but that is alsoo.k. so long as the patient has knowledge of the financialarrangements. The broad definition of fee-splitting says thatpayments to a physician by a health-care related organiza-tion for prescribing or referring a patient is unethical. So, ifa drug company pays you in exchange for prescribing thatcompany’s medication, that is unethical.

Offering or accepting payment for referral of clinicalstudy patients is unethical. Physicians may not chargean excessive fee or an illegal fee. But, what is an exces-sive fee? The measuring stick that the code suggests foran excessive fee is if you have an individual who isknowledgeable about physician fees and that personforms a definitive opinion that this fee is excessive, thenthe fee is deemed excessive, which is not very clear. Ifyou recognize that the average managed care payor reim-burses at 125% of Medicare nationally, this is a muchbetter guideline for what might be an excessive fee. Ifyou’re starting to receive 150% of Medicare, you’re prob-ably starting to tread in excessive fee waters. Certainly


The narrow definition of fee-splitting is a payment

by or to a physician inexchange for a referral.

And that is clearly unethical.It is also illegal in

many states.

when you get to 200% or beyond of Medicare rates, youpossibly should be concerned.

Lab bills should not be marked up. If you send somethingout to the lab, the lab sends it back, you add on your handlingand a little bit extra, you bill it to the patient. This is consideredunethical and illegal in most states. And clearly, for Medicare,if it’s a diagnostic service that you’re sending out, it is illegal.

When a co-payment is a barrier to needed care becauseof financial hardship, physicians should forgive or waive theco-payment. The code says that, but also says: Physiciansshould insure that their policies on co-payments are consis-tent with applicable law and with the requirements of theiragreement with insurers.

Prescriptions should be written solely based upon medicalconsiderations. Receipt of payment or compensation of anykind from a drug company for prescribing its products isunethical. On the other hand, gifts from drug companiesshould primarily entail a benefit to patients or be of nominalvalue when related to the physician’s work.

What about free samples? In 2004, the pharmaceutical indus-try gave away $15.9 billion of free samples. The reason for thisis there is a psychological urge to give back something, that isreciprocity, to give back something to the person who gives yougifts. Does it work? Based on the fact that that $15.9 billion in2004 was double the amount of free drugs that were given outin the 2000, it seems the pharmaceutical industry believes thatthis works. Where does that leave you as the physician from anethical standpoint? Having those free samples available for yourpatients who are less able to afford prescription drugs is a won-derful thing. And taking them puts the patients’ interest first —that acid test of what is ethical behavior. On the other hand,there is a clear statement that says you’re not allowed to takeanything of value from drug companies, particularly when thatmay result in a change in your prescribing habits, which the drugcompanies think that it does. This is not easy to reconcile.

Subsidies to underwrite the cost of CME are permissible,but payments should be directed to the conference spon-sor. Subsidies to defray your cost of attending a meetingare not appropriate.

You can own a pharmacy, but you can’t refer patients to it. Youcan dispense drugs in your office providing that the dispensingprimarily benefits the patient. The AMA also says you cannotcharge to make a profit. Sales of non-health care related itemspresent a conflict of interest, and you shouldn’t sell non-healthcare related items. Selling healthcare related items also pres-ents a conflict of interest and is discouraged. Any products thatare sold must be scientifically efficacious. You have to give fulldisclosure, including your financial arrangement with the manu-facturer. And you should not participate in exclusive dealerships.

PATIENT RECORDS AND ETHICSIf a patient requests that his or her records get trans-

ferred, you must transfer a summary or a photocopy of therecord — no excuses.

You have to deal with patients openly. If you make a med-ical error, the medical ethics require you to disclose fully themedical error that you made so that the patient can appro-priately seek ongoing care to correct the problem. You’reobligated to do this, even if you are presented with legal lia-bility. Your potential legal liability should not be a deterrentto full disclosure with the patient.

Patients need to be notified in advance if you’re going toretire, and you’re supposed notify patients about what you’regoing to do with their medical records. Records may be sold,but you have to notify the patient as to who is going to bethe custodian of the record upon a sale.

Upon leaving a group, the group is required to notifypatients where the doctor who is leaving is going to be prac-ticing in the future. This has a whole range of potentialissues involved in it. For example, what if the contract withthe doctor says the patients are the group’s patients? Doyou still have to let patients know where you are?

An appropriate criteria for retaining a record is whether ornot you would want to see that record upon first examiningthe patient. State laws may require you to retain records fora particular period of time. A record should be kept at leastas long as the statute of limitations.

Unfortunately, that doesn’t tell you anything because inPennsylvania as an example, if I sue in negligence, thestatute of limitation of patients is 2 years. If I sue you as abreach of contract, the statute is 4 years. If I sue you forbreach of warranty, the statute of limitations is 6 years. Andin most states, that time period doesn’t begin to run untilthe patient discovers that malpractice may have been com-mitted, so you don’t know when the time period starts torun. So this ethical pronouncement is unfortunately worth-less in the real world.

Records should be offered to patients before they aredestroyed, and records should be destroyed, not discarded.

ETHICS IN PRACTICEThese are just a few of the many behaviors in which you

engage in a day-to-day practice that you need to approachethically. Clearly, knowing what is right is not always a black-and-white issue, and it requires much thought and consideration.

Mr. Anders, now retired, was with The Health Care Group,

Inc., in Plymouth Meeting, PA.


A Cmd Supplement Final

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