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Pediatric News®

A S U P P L E M E N T T O

IntroductionTor A. Shwayder, MD • Henry Ford Hospital • Detroit

Clinical Presentation of Atopic Dermatitis and Its Differential DiagnosisSeth J. Orlow, MD, PhD • New York University School of Medicine

The Pathophysiology of Atopic Dermatitis and Standard TherapiesRonald C. Hansen, MD • University of Arizona College of Medicine • Tucson

New Therapies for Atopic DermatitisMoise L. Levy, MD • Baylor College of Medicine • Houston

ATOPIC DERMATITIS INTHE PEDIATRIC PATIENT:PATHOPHYSIOLOGY, PRESENTATION, AND AN UPDATE ON NOVEL THERAPIES

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Pediatric News®

The articles in this supplement are

based on presentations made at a

continuing medical education sym-

posium held on October 21, 2002,

in Boston, Mass.

This supplement was supported by

an unrestricted educational

grant from

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ATOPIC DERMATITIS IN THE PEDIATRIC PAPATHOPHYSIOLOGY, PRESENTATION, AND AN UP

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Copyright 2003 International Medical NewsGroup, an Elsevier Science company. All rightsreserved. No part of this publication may bereproduced or transmitted in any form, by anymeans, without prior written permission of thePublisher. The opinions expressed in thissupplement are those of the presenters and do notnecessarily reflect the views of the supporter or thePublisher. International Medical News Groupwill not assume responsibility for damages, loss, orclaims of any kind arising from or related to theinformation contained in this publication,including any claims related to the products,drugs, or services mentioned herein.

Tor A. Shwayder, MDDirector of Pediatric

Dermatology

Henry Ford Hospital

Detroit

Seth J. Orlow, MD, PhDProfessor of Dermatology,

Cell Biology, and Pediatrics

Director of Pediatric

Dermatology

New York University School

of Medicine

Ronald C. Hansen, MDProfessor of Medicine

(Dermatology) and Pediatrics

Director, Pediatric Dermatology

University of Arizona College

of Medicine

Tucson

Moise L. Levy, MDProfessor of Dermatology

and Pediatrics

Baylor College of Medicine

Chief, Dermatology Service

Texas Children’s Hospital

Houston

Faculty

Introduction

Clinical Presentation of Atopic Dermatitis and Its Differential Diagnosis

7 The Pathophysiology of Atopic Dermatitis and Standard Therapies

11 New Therapies for Atopic Dermatitis

16 CME Post-Test and Evaluation


Target AudienceThis activity has been developed for pediatricians and other

health care professionals involved in the treatment of pediatric

atopic dermatitis.

Educational NeedsAtopic dermatitis has become an increasingly prevalent skin con-

dition in infants and children. Pediatricians need to be able to

accurately diagnose the disease and distinguish it from many

other cutaneous dermatoses common to childhood. They also

need to have access to the most current research into the patho-

physiology and epidemiology of atopic dermatitis in order to bet-

ter understand the nature of this chronically relapsing condition.

Pediatricians need to keep abreast of the latest advances in atopic

dermatitis therapy, which allow safe and effective management of

the underlying disease and symptoms, even in infants and young

children.

AccreditationThis activity has been planned and implemented in accor-

dance with the Essential Areas and Policies of the

Accreditation Council for Continuing Medical Education

(ACCME) through the joint sponsorship of Medical Education

Collaborative (MEC) and PEDIATRIC NEWS. Medical Education

Collaborative, a nonprofit education organization, is accredited

by the ACCME to provide continuing medical education for

physicians.

Medical Education Collaborative designates this educational

activity for a maximum of 2 hours of category 1 credit toward the

AMA Physician’s Recognition Award. Each physician should

claim only those hours of credit that he/she actually spent in the

educational activity.

Release date: February 2003

Expiration date: January 2004

RIC PATIENT:AN UPDATE ON NOVEL THERAPIES

D

s

gy

Faculty DisclosuresFaculty/authors must disclose any significant financial interest or

relationship with proprietary entities that may have a direct

relationship to the subject matter. They must also disclose any

discussion of investigational or unlabeled uses of products.

Dr. Hansen is a consultant to, is on the advisory board of, and

has received honoraria from Novartis Pharmaceuticals

Corporation. Dr. Orlow is a consultant to and has received

honoraria from Novartis. Dr. Levy has received clinical research

support from and is a consultant to Fujisawa Healthcare and

Novartis and he has received honoraria from Fujisawa, Galderma

Laboratories, L.P. and Novartis. He discusses the unlabeled use of

pimecrolimus in children under the age of 2. Dr. Shwayder has

nothing to disclose.

Learning ObjectivesBy reading and studying this supplement, participants should be

able to:

• Identify the major diagnostic criteria for atopic dermatitis

and describe the age-determined patterns seen in infants and

children.

• Distinguish atopic dermatitis from other cutaneous diseases

common to the pediatric patient who presents with erythe-

ma, papulation, and/or scale.

• Describe the pathophysiology of atopic dermatitis and list

immunoregulatory abnormalities commonly associated with

the condition.

• Name the most common exacerbants and triggers of atopic

dermatitis.

• Summarize conventional treatment options, their benefits,

and their limitations.

• Describe the mechanism of action of steroid-free topical

immunomodulators.

• Summarize the findings of clinical trials that have examined

the efficacy and safety of the new steroid-free agents.


4 Atopic Dermatitis in the Pediatric Patient

o definitive laboratory tests currently exist to diagnose

atopic dermatitis, nor are the lesions themselves pathog-

nomonic. Diagnosis of atopic dermatitis is based solely

on clinical criteria, which include factors such as lesion

appearance, distribution, and duration; history of the illness;

symptoms; and family medical history.

Atopic dermatitis is distinguished by erythema, papulation,

excoriation, and lichenification. Pruritus is the first symptom,

followed by erythema and papulation. External factors such as

scratching, rubbing, and irritation cause the excoriation and

lichenification of the skin that are often seen.

N

CLINICAL PRESENTATION OF ATOPIC DERMATITISAND ITS DIFFERENTIAL DIAGNOSIS

Seth J. Orlow, MD, PhD

Atopic dermatitis can be characterized by age-determined pat-

terns. The disease can be thought of as having infantile, child-

hood, and adolescent/adult stages. In young infants, erythema

and raised papules are the chief characteristics seen, and involve-

ment typically occurs on the cheeks, forehead, and scalp. The

extensor surfaces of the arms and legs often are affected. The

infant may be quite itchy and miserable but too young to possess

the ability to scratch the affected areas. Parents are often surprised

to learn that their child is itchy since they do not see the infant

scratching. Atopic infants too young to scratch will typically rub

the area bothering them. When the infant becomes able to

scratch or rub persistently, the affected area may evolve into ery-

thematous, scaling, oozing, crusty patches, and plaques.

The diaper area of an infant with atopic dermatitis is typically

spared. If atopic dermatitis is evident in the diaper area, this may

suggest that food allergies are responsible. According to Sicherer

and Sampson,1 approximately 40% of children with moderate to

severe atopic dermatitis have food allergies. However, it is unclear

what role the allergy plays in provoking a flare of atopic dermati-

tis in the majority of children.

In the childhood stage, atopic dermatitis is most likely to

appear on the flexor surfaces—antecubital and popliteal fossae,

wrists, ankles, and neck.2 If the disease is not controlled, scratch-

ing causes the skin to thicken, lichenification begins to occur, and

pigmentary changes may become evident (Figure 1).

Many pediatric patients do “outgrow” the disease. Even in

those who do not, the condition typically ameliorates over time.

INTRODUCTION

ne of the more common sights to be found at a pedia-

trician’s office is a parent accompanied by a child who is

described as “red and itchy.” Is it atopic dermatitis or a

host of other cutaneous conditions that present with

similar symptoms? Atopic dermatitis is a disease estimated to

affect 10% to 20% of children.1 It has a characteristic presenta-

tion but no definitive laboratory tests.

In these pages, Seth J. Orlow, MD, PhD, reviews the major

and minor clinical criteria needed to make a diagnosis of atopic

dermatitis, with special emphasis on infantile and childhood pre-

sentations of the disease. He provides insight on how to make the

differential diagnoses between atopic dermatitis and conditions

with which it might be confused, such as seborrheic dermatitis,

allergic contact dermatitis, scabies, and psoriasis. Ronald C.

Hansen, MD, reviews the prevalence and pathophysiology of

O

Tor A. Shwayder, MD

atopic dermatitis and factors thought to exacerbate the condition

and summarizes the benefits and limitations of conventional

treatment, which currently comprises a constellation of cortico-

steroid, emollient, antibiotic, and allergen-avoidance therapies.

In his presentation, Moise L. Levy, MD, focuses on the novel

calcineurin inhibitors that offer a corticosteroid-free option for

those concerned about skin atrophy and other side effects of top-

ical corticosteroid use. He reviews the many recent short-term

and long-term safety and efficacy trials of the topical

immunomodulators tacrolimus and pimecrolimus in infants,

children, adolescents, and adults.

Reference1. Schultz-Larsen F, Hanifin JM. Epidemiology of atopic dermatitis.

Immunol Allergy Clin North Am. 2002:22:1-24.

Lichenification in atopic dermatitis is characterized by skin thickeningand the exaggeration of normal skin markings. Pigmentary changesare particularly evident in patients with darker skin.Courtesy of Seth J. Orlow, MD, PhD

Figure 1. Lichenified Atopic Dermatitis


Atopic Dermatitis in the Pediatric Patient 5

It is recommended that physicians not tell parents that their

child’s atopic dermatitis will disappear by a certain age, because it

is impossible to predict which patient will have persistent disease.

A useful analogy pediatricians can use for parents is that atopic

dermatitis prevalence is shaped like a pyramid, with infants at the

bottom and adults at the top.

Atopic dermatitis after puberty implies a higher risk of lifelong

involvement. In adults, atopic dermatitis most commonly occurs

on the face, hand, or antecubital regions. This discussion, how-

ever, will focus primarily on atopic dermatitis in the pediatric

patient.

Diagnostic Criteria for Atopic DermatitisFormal diagnostic criteria have been

established for the diagnosis of atopic der-

matitis. They are typically used in a

research setting. Many of them are varia-

tions of the Hanifin-Rajka criteria, estab-

lished during the First International

Symposium on Atopic Dermatitis, in

1979.3 According to these criteria, three of

the following four major features must

be present for a diagnosis of atopic

dermatitis:

• Pruritus, often severe

• Morphology and distribution that includes facial and/or

extensor involvement in infants and flexor and/or neck

involvement in children

• Chronically relapsing course

• Personal or family history of atopy (eg, allergic rhinitis,

allergic conjunctivitis, asthma)

Pruritus is the hallmark of the disease, whether or not the

patient is old enough to scratch the affected area or voice the

complaint. Parents are often disappointed to learn that atopic

dermatitis is chronically relapsing and that there is no magic cure

that will permanently eradicate their child’s condition.

In addition to having at least three major features, the patient

should exhibit at least three of these minor features, which have

been grouped into three broad categories:

Common/General

• Xerosis

• Ichthyosis vulgaris/keratosis pilaris/palmar hyperlinearity

• Early age of onset

• Tendency toward cutaneous infections/impaired cell-

mediated immunity

• Tendency toward nonspecific hand or foot dermatitis

• Nipple eczema

• Erythroderma

Facial/Ocular

• Cheilitis of upper lip

• Recurrent conjunctivitis

• Infraorbital (Dennie-Morgan) fold/orbital darkening

• Keratoconus

• Posterior/anterior subscapular cataracts

Hyperreactivity

• Increased levels of serum immunoglobulin E (IgE)

• Positive (type 1) hypersensitivity on skin tests

• Peripheral blood eosinophilia

It should be noted that although elevated serum IgE is a com-

mon finding in atopy, approximately 20% of patients with atopic

dermatitis have normal levels.4 A patient’s parents may be

confused by the classification of atopic dermatitis as an “allergic”

disorder, since it may lead to the erroneous conclusion that iden-

tification of a single or multiple allergic agents can “cure” their

child’s disease. A better way to describe the child’s condition is to

explain that atopic dermatitis is not an allergy to any one thing

but a “supersensitivity” to myriad provocational factors, many of

them irritant in nature.

Nummular dermatitis lesions are some-

times seen in pediatric patients with atopic

dermatitis. The lesions appear as round,

fixed, very itchy plaques that are thicker than

the sites of atopic dermatitis elsewhere on

the child’s body. They sometimes can be mis-

taken for psoriasis because they are thick and

scaly like psoriatic lesions, but there is usual-

ly other evidence of atopic dermatitis

present. Nummular dermatitis also can be

distinguished from tinea corporis by the fact

that unlike those characteristic of tinea corporis, nummular lesions

are multiple, symmetric, and lacking in pustules and evidence of

central healing. The condition can be distinguished from impetigo

lesions in that nummular dermatitis lesions, although sometimes

crusted, are clearly thick inflammatory plaques.

Infectious Complications of Atopic DermatitisSome lesions that appear on the skin of children with atopic der-

matitis are the result of infections of the disease. The major infec-

tious complications of atopic dermatitis are eczema herpeticum,

molluscum contagiosum, and impetigo.

Eczema herpeticum is caused by the spread of herpes simplex

virus into atopic dermatitis lesions. Eczema herpeticum, also

known as Kaposi’s varicelliform eruptions, appears as 2- to 3-mm,

punched-out, hemorrhagic erosions that skip from one area of der-

matitis to another. A primary herpetic infection may be accompa-

nied by fever, malaise, and lymphadenopathy. The most serious

complication in a normal host is risk of keratitis. Because it also

predisposes to the spread of smallpox, atopic dermatitis is a con-

traindication to smallpox vaccination.

Molluscum contagiosum is the most common viral complication

of atopic dermatitis. These dome-shaped papules have a caseous

core. The papules, which can appear in large numbers in atopic

patients, are typically flesh-colored but can be inflamed and erythe-

matous. Sometimes they are surrounded by eczematous patches. In

pediatric patients with atopic dermatitis, outbreaks typically occur

along the flanks and the antecubital and popliteal fossae.

Impetigo is a common bacterial complication of atopic dermati-

tis (Figure 2, page 6). It has been known for 40 years that atopic

“...atopic dermatitisis not an allergy toany one thing but a‘supersensitivity’ to

myriad provocationalfactors, many of them

irritant in nature.”

y

y



patients have substantial quantities of Staphylococcus aureus in their

skin, particularly in the regions where they experience flares, so it

is not surprising that they are more prone to bacterial skin infec-

tion. Impetigo is characterized by vesicles or bullae with straw-col-

ored discharge that dries to form a thick crust.

Distinguishing Atopic Dermatitis From Four Common Conditions

Many dermatoses resemble atopic dermatitis, at least superfi-

cially. Some conditions with which it can be confused include

seborrheic dermatitis, allergic contact dermatitis, scabies, and

psoriasis. However, there are frequently clues, such as disease his-

tory or lesion distribution, that can aid the physician in distin-

guishing them from atopic dermatitis.

Infantile seborrheic dermatitis, commonly known as cradle

cap, has an earlier onset than atopic dermatitis. Pruritus is usual-

ly lacking. It may be present on the face, ears, scalp, and trunk,

where one often sees atopic dermatitis, but it may also appear in

skinfolds, axillae, and groin—sites where atopic dermatitis usual-

ly is not found. It is typified by the presence of a greasy yellow

scale. If the pediatrician is unable to distinguish it from atopic

dermatitis during the first office visit, having the child return for

a second visit to see how the condition has responded to treat-

ment is usually sufficient to make the correct diagnosis.

Allergic contact dermatitis is an eczematous dermatitis, but it

is not atopic dermatitis. Common causes are exposure to poison

ivy or nickel (contained in items such as jewelry or belt buckles).

It may have a sudden onset or appear insidiously, and it may

exhibit an unusual distribution. For example, a patient may have

a square patch of dermatitis on one arm from exposure to tape

used to secure an intravenous line, or inflammation on an earlobe

where a nickel-containing gold earring stud was inserted.

Key features that distinguish scabies from atopic dermatitis are

that, in addition to papules, small linear burrows and sometimes

nodules are present. Scabies is caused by skin infestation by a

mite and spreads easily in infants and immunocompromised

patients, so there can be large-scale involvement along the flanks,

wrists, ankles, palms, soles, and scalp. Older children and adults

may have scabies on their finger webs, wrists, axillae, and groin.

Another clue to the diagnosis of scabies may be that pruritus is

not limited to the patient but may include other family members

or those who have come in close contact. Microscopic examina-

tion of skin scrapings can reveal the presence of the mite, her eggs,

or feces.

The morphology of psoriasis is also different from that of

atopic dermatitis. In psoriasis, well-circumscribed lesions consist

of pink plaques topped with silvery white scale. Tearing the scale

off a psoriatic plaque will reveal the Auspitz sign—multiple fine

bleeding points caused by thinning of the epidermis over the der-

mal papillae. There is typically less pruritus with psoriasis than

with atopic dermatitis. Distribution is symmetric, with lesions

found on extensor extremities, behind the ears, on palmar/plantar

skin, and on the scalp. One would not expect to find atopic der-

matitis or seborrheic dermatitis on the palms and soles. Younger

children can have facial involvement. Psoriasis can also be found

in the diaper area, where atopic dermatitis is uncommon.

Less Common Differential DiagnosesLess common dermatoses that may occasionally need to be dis-

tinguished from atopic dermatitis include dermatophytosis (tinea

corporis), drug eruptions, dermatomyositis, and cutaneous T-cell

lymphoma.

It is important to recognize tinea corporis because the topical

corticosteroids used to treat atopic dermatitis will worsen a fungal

infection. Tinea lesions typically have an asymmetric, scaly border

with central clearing. Sometimes there are pustules. Diagnosis can

be confirmed by performing a culture.

Certain medications can trigger erythema and pruritus in some

patients. A full review of drug reactions in children has recently

been published.5 Dermatomyositis may at first be mistaken for

atopic dermatitis because there is typically some facial involve-

ment, including the eyelids. However, violaceous papules on the

knuckles are pathognomonic for dermatomyositis. Edema in the

periorbital tissue and sun provocation are also characteristic of

that disease. In pediatric patients, muscle weakness and calcinosis

of subcutaneous tissue are common.

Cutaneous T-cell lymphoma is extremely rare in children and

encompasses several non-Hodgkin’s lymphomas that present

initially in the skin, including mycosis fungoides and its

leukemic phase, Sézary syndrome. Mycosis fungoides first appears

as erythematous scaly patches that are few in number and typi-

cally distributed on the trunk or limb girdle area. These persis-

tent, pruritic patches may be mistaken for atopic dermatitis at

first. Skin biopsy of suspicious lesions can confirm diagnosis of

mycosis fungoides.

ConclusionAlthough atopic dermatitis cannot be diagnosed definitively

by laboratory tests or pathognomonic lesions, the disease is

Continued on page 15.

Staphylococcus aureus is the pathogen most likely to cause impetigo in patients with atopic dermatitis. The cutaneous lesions are character-ized by pus-filled vesicles that rupture. The thick, pale-yellow dischargedries and crusts.Courtesy of Seth J. Orlow, MD, PhD

Figure 2. Infectious Complications of Atopic Dermatitis: Impetigo



THE PATHOPHYSIOLOGY OF ATOPIC DERMATITISAND STANDARD THERAPIES

Ronald C. Hansen, MD

topic dermatitis (AD) is a chronic inflammatory skin

disease that has experienced increasing prevalence over the

past 40 years in industrialized countries. Recent studies of

atopic dermatitis in pediatric populations have found rates

of 17.2% in the United States (among children 5 to 9 years of age),

15.6% in northern Europe (children 7 years of age), and 19% in

Japan (children 7 to 9 years of age).1,2,3 A study of childhood preva-

lence of atopic dermatitis in 56 countries found wide variations

within and between countries, affecting approximately 5% to 20%

of children at 6 to 7 years and 13 to 14 years of age.4 The authors

concluded that the disease is a major public health problem

worldwide.

Approximately half of all cases of atopic

dermatitis are diagnosed before 1 year of age,

and 80% are diagnosed by 5 years of age.5

Although atopic dermatitis will remit in a

majority of children by the time they reach

puberty, this is small comfort to the parents

of an infant or toddler whose skin is ravaged

by severe disease. In its severest manifesta-

tions, atopic dermatitis can cause failure to

thrive.6 Children besieged by pruritus have

little interest in eating, and their appetite is

further suppressed by the release of

cytokines, including tumor necrosis factor, that have a cachectic

effect. They also lose substantial amounts of albumin from exfoli-

ated skin. According to one study, school-aged children with

moderate to severe atopic dermatitis are at high risk of developing

psychological difficulties.7 Although there is no cure for atopic der-

matitis, there are, fortunately, many more tools available today to

help control and manage its flares.

Pathogenesis and Immunology of Atopic Dermatitis

The precise pathogenesis of atopic dermatitis is unclear;

however, genetics and environmental factors are both thought to

play a role. There is also evidence to suggest that atopic individu-

als exhibit altered local immune responses to many different stim-

ulants, including antigens.

Approximately 60% to 70% of children with atopic dermatitis

have a family history of atopy (eg, asthma, allergic rhinitis, atopic

dermatitis).8 A substantial number of children have no obvious

family history of atopic disease, however. One way to explain the

condition to parents, whether there is a family history or not, is

that the child has genetically determined itchy skin.

According to Leung,9 the following immunoregulatory abnor-

malities are characteristic of patients with atopic dermatitis

(Table 1):

• Increased levels of serum

immunoglobulin E (IgE)

• Eosinophilia

• Increased spontaneous histamine

release from basophils

• Chronic macrophage activation

• Increase in interleukin (IL)-4– and

IL-5–secreting T-helper type 2 (TH2)

cells

• Decrease in interferon (IFN)-�–

secreting TH1 cells

The increased IgE response and eosinophilia seen in atopic

dermatitis reflect the increased expression of TH2 cytokines, and

these factors plus the histamine release from basophils increase

the pruritus and inflammation experienced by the patient.

The central mechanisms by which atopic dermatitis initiates

are believed to be as follows: Langerhans’ cells, which are den-

dritic antigen-presenting cells in the epidermis, hyperstimulate T

cells, perhaps in response to specific antigens.10 As indicated in

the list of immunologic findings above, the two subtypes of T

cells primarily affected are TH2 cells, associated with acute atopic

dermatitis, and TH1 cells, associated with chronic disease.

After the activated Langerhans’ cell, which has IgE bound to

it, presents the antigen to the T cells, a number of processes

begin to occur, including calcineurin phosphatase, which Dr.

Levy discusses in more detail elsewhere in this supplement, that

activates T cells. In acute atopic dermatitis, TH2 cells infiltrate

the dermis. The TH2 response is accompanied by increased IgE

levels and expression of IL-4 and IL-5 and manifests clinically

and histologically with papulation and spongiosis. Histamine

release plays only a small role in this T-cell activation process,

which is why antihistamines are relatively ineffective in treating

atopic dermatitis.

As the disease progresses from an acute to a chronic phase,

there is a biphasic switch from TH2 to TH1 cellular response,

A

“Approximately halfof all cases of atopic

dermatitis are diagnosed before 1 year of age, and80% are diagnosedby 5 years of age.”

Table 1. Systemic Immune Findings in Atopic Dermatitis

• Increased serum IgE• Eosinophilia• Increased spontaneous histamine release

from basophils• Chronic macrophage activation• More IL-4/IL-5–secreting TH2 cells• Fewer IFN�-secreting TH1 cells

(but greater role in chronic stages)Adapted from: Leung DYM. J Allergy Clin Immunol. 2000;105:860-876



accompanied by the clinical/histologic evidence of lichenifica-

tion, epidermal hypertrophy, and dermal fibrosis.

Exacerbants and Triggers of Atopic DermatitisA person with atopic dermatitis has skin that is hyperirritable.

A number of factors can cause the disease to relapse or worsen.

Known exacerbants and triggers include anxiety and stress, cli-

matic factors, irritants, allergens, and infection (Table 2).

Psychosocial factors such as anxiety and stress influence the

disease process of atopic dermatitis. The relentless pruritus of

active disease can create a vicious cycle by evoking irritability and

sleep disturbance that further erode a patient’s emotional state.

Changes in both temperature and humidity can affect the dis-

ease. Patients’ atopic dermatitis may worsen in winter, when the

air is cold and dry. The warm, arid air of desert climes (and

indoor heating) similarly may heighten pruritus by causing xero-

sis. Excessively warm, moist air can be equally irritating to atopic

patients because it triggers perspiration that leaves skin desiccat-

ed and/or pruritic.

Patients with atopic dermatitis have reduced tolerability to

irritants, which can be either chemical or physical. The most

common irritant is water. Any water exposure—swimming,

showering, repeated hand washing—is ultimately drying to the

skin, unless an emollient is applied immediately afterward to trap

moisture in the stratum corneum. As already noted, water in the

form of perspiration is drying to the skin. Soaps, detergents, per-

fumes, and solvents are examples of chemical irritants. Wool and

other rough material, including synthetics, fall into the category

of cutaneous contact irritants.

Contact allergic reactions to certain substances (eg, cosmetics

and topical medications) can provoke recurrence of atopic der-

matitis. The degree to which aeroallergens (particularly pollen

and house dust mites) and food allergens are atopic dermatitis

cofactors is the subject of an ongoing debate. Although a large

number of patients with atopic dermatitis also have respiratory

and food allergies, the role such allergies play in the actual

pathogenesis of atopic dermatitis is unclear. There is certainly no

harm in experimenting with elimination diets for foods most

likely to cause allergic reactions (eg, eggs, milk, peanuts, soy, and

wheat), as such reactions may complicate allergic dermatitis in a

subset of sensitized patients. However, it is recommended that

elimination diets be done in conjunction with, not in lieu of,

other therapies for atopic dermatitis.

The primary microbial allergen is Staphylococcus aureus. It is

found in more than 90% of patients with atopic dermatitis lesions;

in contrast, only 5% of healthy subjects harbor the organism on

their skin.9 Because of the pervasiveness of S. aureus in atopic

patients, a positive culture does not necessarily indicate a clinically

relevant infection. However, it appears that the organism may

worsen atopic dermatitis even when it does not cause obvious

infection. Lever et al11 found that topical antibiotic treatment

reduced clinical severity in patients with atopic dermatitis even in

the absence of overt infection. Fungal infection from Malassezia

furfur (also called Pityrosporum ovale) also has been implicated as a

pathogen in atopic dermatitis. These ubiquitous lipophilic yeasts

are associated with immune response in atopic dermatitis, especial-

ly head and neck dermatitis.12 However, the role of these yeasts in

causation and exacerbation of atopic dermatitis is much more con-

troversial than the role of S. aureus.

Pruritus Control Is KeyIt is often said of atopic dermatitis that it is not the rash that

itches, but the itch that rashes. Patients with atopic dermatitis

have a lower itch threshold. In addition to the environmental,

allergenic, and infectious exacerbants discussed, the itch-scratch

cycle is intrinsic to the perpetuation of atopic dermatitis. In the

itch-scratch cycle, pruritus invokes scratching, scratching causes

skin trauma and excoriation, which then lead to inflammation

and more pruritus. Chronic inflammation and scratching lead to

lichenification of the skin.

Controlling the patient’s pruritus, therefore, is paramount to

disease management. The itch-scratch cycle must be interrupted.

Because pruritus precedes the visible eruption, therapy should be

initiated then.

Xerosis, or abnormally dry skin, is a common complaint of

atopic dermatitis and a source of pruritus on its own. Xerosis occurs

in 48% to 98% of patients with atopic dermatitis.13 Atopic skin has

Table 3. Therapies for Atopic Dermatitis

• Combination therapy for effective control– Emollients– Irritant and allergen avoidance– Antihistamines– Topical corticosteroids (first-line therapy)– Antibiotics– Phototherapy (eg, PUVA)– Immunosuppressive/immunomodulatory therapy– Corticosteroid-free agents

PUVA= psoralen plus ultraviolet AAdapted from: Beers MH, Berkow R, eds. Dermatitis. In: The Merck Manual of Diagnosis andTherapy. 17th ed. Rahway, N.J.: Merck Research Laboratories; 1999:816-818.

Table 2. Exacerbants and Triggers

• Anxiety/stress

• Climate factors– Temperature– Humidity

• Irritants– Detergents, solvents– Wool or other rough material– Perspiration

• Allergens (contact, inhaled, and possibly food)

• Infection (staph)

Adapted from: Glickman FS. In: Clinics in Dermatology. Greenwich, Conn.: Conn.

Postgraduate Healthcare. Berkow R, Fletcher AJ, eds. Dermatitis. In: The Merck Manual of

Diagnosis and Therapy. 16th ed. Rahway, N.J.: Merck Research Labs, 1992:2407-2415.



been found to have reduced water-binding capacity. When water

content of the stratum corneum is decreased, skin barrier function

is impaired and the skin is more easily irritated and pruritic.

As noted previously, atopic skin is hyperirritable, and certain

conditions may trigger pruritus in the atopic patient that would

not affect others, such as perspiring after exertion or exposure to

perfumes, cosmetics, soaps, or other prod-

ucts.

Standard Therapies for AtopicDermatitis

Combination therapy appears to be the

most effective control for atopic dermati-

tis, and the physician’s treatment arsenal

includes emollients, avoidance of triggers,

antihistamines, topical corticosteroids,

antibiotics, phototherapy, and immuno-

suppressive therapy, as well as the new

corticosteroid-free topical agents Dr. Levy discusses in detail

elsewhere in this supplement (Table 3).

Emollients

Emollients are a mainstay of atopic dermatitis therapy. They

restore moisture to the epidermis and help relieve pruritus. Lucky

et al14 found emollients to be corticosteroid-sparing in the

treatment of mild to moderate atopic dermatitis in a pediatric

population. Emollients should be applied routinely and after

every skin-drying experience such as showering, swimming, or

physical activity that generates heavy perspiration. Even when

topical corticosteroids are used on lesions, emollients should be

applied to uninvolved skin.

Corticosteroids

Topical corticosteroids have represented the traditional first-

line therapy for many years. Used correctly, these antiinflamma-

tory agents are effective, inexpensive, and relatively safe.

Corticosteroids are ranked by potency into seven classes. To avoid

potential side effects, it is recommended that one use the least

potent corticosteroid that will interrupt the itch-scratch cycle;

only low-potency formulations should be used on the face, groin,

skinfolds, and axillae.

Topical corticosteroids have many limitations, however

(Table 4). One is tachyphylaxis. After extended use, these agents

lose some of their effectiveness. Problems associated with long-

term use of corticosteroids, although rare, include serious skin

side effects such as atrophy, telangiectasia, and striae. If cortico-

steroids are applied to the eyelid or periorbital area, there is a risk

of cataract and glaucoma. Systemic side effects such as hypothal-

amic-pituitary-adrenal (HPA)–axis suppression represent a special

risk in pediatric populations, because children have a higher body

surface area-to-weight ratio than adults.

Steroid phobia is another limitation of corticosteroid therapy.

Although corticosteroids are relatively safe when used correctly,

parental, patient, and, to some extent, physician concern over

their toxicity affects compliance. Charman et al15 found that 73%

of patients worried about using topical corticosteroids on them-

selves or on their children, and 24% admitted to noncompliance

due to these concerns. The concern over side effects also causes

physicians to convey an inconsistent message. Parents are told to

use the corticosteroids on their children to stop the rash, but to

stop before side effects occur. They find these instructions con-

fusing and halt therapy prematurely, resulting in undertreatment

and a child with poorly controlled disease.

One way to combat steroid phobia, if the

parents cannot be convinced that these

products can be used safely, is to switch to

one of the corticosteroid-free agents now

available.

Oral corticosteroids have proven to be

effective and fast-acting in treating atopic

dermatitis, but there are toxicity issues with

repeated use. Another limitation is that

their effectiveness tends to derail the topical

program that needs to accompany the oral

therapy. The children get better right away, so the parents do not

see the need to embark on the labor-intensive process of applying

emollients and topical corticosteroids, administering hydrother-

apy, and taking the other steps involved to prevent flare

recurrence. In this pediatric dermatologist’s experience, oral corti-

costeroids are reserved for emergency therapy.

Other therapies

Avoidance of food and inhalant allergens, chemical and

mechanical irritants, and other triggers, such as stress or tempera-

ture extremes, can be beneficial but is not always possible. Oral

antihistamines are often used to treat pediatric patients and are

thought to work primarily through sedating the patient, providing

relief from nocturnal scratching. (For this reason, it is unclear

whether the newer nonsedating antihistamines are effective in treat-

ing atopic dermatitis.) Topical antihistamines have not demonstrat-

ed much benefit and pose the risk of cutaneous sensitization.

Antibiotics are likely underused in the treatment of atopic

dermatitis. As noted previously, these agents can be effective in

treating the disease even in patients with no obvious bacterial

Table 4. Limitations of Topical Corticosteroid Therapy

• Efficacy (tachyphylaxis)

• Skin side effects– Atrophy– Telangiectasia– Striae

• Risk of cataract and glaucoma (eyelid application)

• HPA-axis suppression– Since children have higher body surface area

(BSA)-to-weight ratio than adults, they are moreprone to systemic steroid effects

Adapted from: Leung DY, et al. Ann Allergy Asthma Immunol. 1997;79:197-211. Hepburn D,et al. Adv Dermatol. 1994;9:225-254.

“Combination therapy appears to be the most

effective control for atopic

dermatitis...”



infection. Viral pathogens, addressed elsewhere in this supple-

ment by Dr. Orlow, also need to be treated when present, as do

fungal pathogens, which increase the risk of dermatophyte

infections in atopic dermatitis.16

Phototherapy using ultraviolet light is sometimes prescribed

for patients with recalcitrant disease.17 Studies investigating

immunosuppressive therapy (eg, cyclosporine) for treatment of

atopic dermatitis have shown mixed results. The therapy may

be better suited for adults than for pediatric patients.

Mentholated lotions, which counterstimulate and distract the

patient, may provide temporary relief but do not provide real

therapeutic benefit. Topical cromolyn has been investigated for

its antipruritic benefit for atopic patients, but it cannot

penetrate the epidermis sufficiently to inhibit mast cell

degranulation.

ConclusionAtopic dermatitis is a disease with a poorly understood patho-

genesis and is best treated with a combination of therapies.

Conventional treatment therapies all have limitations, and most

patients with moderate to severe disease are inadequately treated.

Atopic dermatitis has a significant impact on the quality of life

and psychosocial health of the pediatric patient and on the

patient’s family as well.

References1. Laughter D, Istvan JA, Tofte SJ, Hanifin JM. The prevalence of

atopic dermatitis in Oregon schoolchildren. J Am Acad Dermatol.

2000;43:649-655.

2. Schultz-Larsen F, Diepgen T, Svensson A. The occurrence

of atopic dermatitis in North Europe: An international question-

naire study. J Am Acad Dermatol. 1996;34:760-764.

3. Sugiura H, Umemoto N, Deguchi H, et al. Prevalence of child-

hood and adolescent atopic dermatitis in a Japanese population:

Comparison with the disease frequency examined 20 years ago.

Acta Derm Venereol. 1998;78:293-294.

4. Williams H, Robertson C, Stewart A, et al. Worldwide variations

in the prevalence of symptoms of atopic eczema in the interna-

tional study of asthma and allergies in childhood. J Allergy Clin

Immunol. 1999;103:125-138.

5. Leung DYM. Atopic dermatitis: Immunobiology and treatment

with immune modulators. Clin Exp Immunol. 1997;107(suppl

1):25-30.

6. Abrahamov A, Schifmann R, Goldstein R, et al. Growth failure

due to protein loss in dermatitis. Eur J Pediatr. 1986;145:223-

226.

7. Absolon CM, Cottrell D, Eldridge SM, Glover MT. Psychological

disturbance in atopic eczema: The extent of the problem in

school-aged children. Br J Dermatol. 1997;137:241-245.

8. Svensson A. Diagnosis of atopic skin disease based on clinical cri-

teria. Thesis. Kristionsted: Bohlins Grafiska, 1989.

9. Leung DYM. Atopic dermatitis: New insights and opportunities

for therapeutic intervention. J Allergy Clin Immunol. 2000;105:

860-876.

10. Hanifin JM, Chan S. Biochemical and immunologic mechanisms

in atopic dermatitis: New targets for emerging therapies. J Am

Acad Dermatol. 1999;41:72-77.

11. Lever R, Hadley K, Downey D, Mackie R. Staphylococcal colo-

nization in atopic dermatitis and the effect of topical mupirocin

therapy. Br J Dermatol. 1988;119:189-198.

12. Jensen-Jarolim E, Poulsen L, With H, et al. Atopic dermatitis of

the face, scalp, and neck: Type 1 reaction to the yeast

Pityrosporum ovale? J Allergy Clin Immunol. 1992;89:44-51.

13. Linde YW. Dry skin in atopic dermatitis. Acta Derm Venereol.

Suppl (Stockh). 1992;177:9-13.

14. Lucky AW, Leach AD, Laskarzewski P, Wenck H. Use of an emol-

lient as a steroid-sparing agent in the treatment of mild to mod-

erate atopic dermatitis in children. Pediatr Dermatol. 1997;14:

321-324.

15. Charman CR, Morris AD, Williams, HC. Topical corticosteroid

phobia in patients with atopic eczema. Br J Dermatol. 2000;

142:931-936.

16. Rudikoff D, Lebwohl M. Atopic dermatitis. Lancet. 1998;

351:1715-1721.

17. Leung DY, Hanifin JM, Charlesworth EN. Disease management

of atopic dermatitis: A practice parameter. Ann Allergy Asthma

Immunol. 1997;79:197-211.



opical corticosteroids are the cornerstone of conventional

treatment for atopic dermatitis at present, as Dr. Hansen

has described elsewhere in this supplement, but new treat-

ment therapies have recently been introduced that show

promising results in some short-term and long-term pediatric

studies.

This discussion focuses on two topical corticosteroid-free

immunomodulatory agents, tacrolimus and pimecrolimus.

Tacrolimus, formerly known as FK506, is the older of the two

drugs. It was approved for atopic dermatitis treatment by the U.S.

Food and Drug Administration in late 2000. Tacrolimus was first

developed to prevent allograft rejection in liver and kidney trans-

plant recipients and is still used for that purpose. Pimecrolimus, an

ascomycin derivative formerly known as SDZ ASM 981, was

approved approximately 1 year later. It was the first immunomod-

ulatory therapy to be developed specifically to treat inflammatory

skin diseases.

Calcineurin Inhibitors: Similarities and Differences

Both tacrolimus and pimecrolimus are commonly referred to

as immunomodulatory drugs or antiinflammatory agents. The

term that best describes their mechanism of action might be

topical calcineurin inhibitors. As Dr. Hansen notes in his dis-

NEW THERAPIES FOR ATOPIC DERMATITIS

Moise L. Levy, MD

cussion, atopic dermatitis originates from an inflammatory

cascade resulting from T-cell hyperstimulation from antigen-

presenting cells. Both tacrolimus and pimecrolimus have the

ability to bind with a specific immunophilin or macrophilin

and then to calcineurin. This effectively blocks the dephospho-

rylation of the nuclear factor of activated T cells (NF-AT),

which is a necessary step in activating the T cells that generate

the proinflammatory cytokines.

Tacrolimus and pimecrolimus have very similar chemical

structures. However, the small structural differences that distin-

guish them from one another can lead to a host of important

differences in pharmacologic activity.

Meingassner et al1 compared pimecrolimus with tacrolimus in

murine and rat models of T-cell–mediated skin inflammation

(allergic contact dermatitis). The same study also compared the

two agents in systemic immunosuppression (graft-vs-host and

kidney transplant rat models) (Figure 1). Pimecrolimus was

found to be as effective as tacrolimus in skin inflammation mod-

els. In the immunosuppression models, however, pimecrolimus

was found to have a low potential for affecting systemic immune

responses, in contrast to tacrolimus. These findings indicate that

pimecrolimus, unlike tacrolimus, has a skin-selective pharmaco-

logic profile. Research by Bilich et al2 showed pimecrolimus to be

more lipophilic and permeate less through rat, pig, and human

Figure 1. Pimecrolimus vs Tacrolimus in Systemic Immunosuppression

T

0

1

2

3

4

5

ACD rat ACD mouse Graft vs host Kidney transplant

>2

1/66 1/15

Skin inflammation models

Potency Relative to Tacrolimus in Animal Models

Equivalence

Systemic immunosuppression models

oral oral sc oral

ACD = allergic contact dermatitis;sc = subcutaneous.

1

Pim

ecro

limus

: ta

crol

imus

Adapted from Meingassner JG et al. (inflammation/immunosuppression models),Presented at AAD 60th Annual Meeting, February 2002, New Orleans, La.



Figure 2. Infantile Atopic Dermatitis

skin than tacrolimus, suggesting that pimecrolimus offers a lower

risk of systemic exposure.

In open-label pharmacokinetic studies of pediatric patients

(3 months to 14 years of age) with moderate to severe atopic

dermatitis treated with pimecrolimus 1% cream, blood concen-

trations of pimecrolimus were found to be consistently low

(99.2% <2 ng/mL) regardless of age, extent of skin area treated

(19% to 92% of body surface area), and duration of therapy (up

to 1 year).3 Even after oral administration of pimecrolimus, a reg-

imen under examination as a treatment for psoriasis in adults,

blood concentrations were found not to exceed 55 ng/mL.4 No

systemic accumulation was seen over a 12-month duration in

any of these studies.

Short-Term Studies Show Calcineurin Inhibitors Provide Fast Results

The effectiveness of both tacrolimus and pimecrolimus, com-

pared to vehicle, has been investigated in short-term studies of

adult and pediatric patients.

Tacrolimus

Paller et al5 evaluated topical tacrolimus at two different

concentrations (0.03% and 0.1%) vs vehicle in a randomized,

double-blind, 12-week study of 351 children 2 to 15 years of age

who had moderate to severe atopic dermatitis. The primary effi-

cacy end point was physician global assessment. Patients were

evaluated at baseline and at weeks 1, 2, 3, 6, 9, and 12.

Significantly more patients (P<0.001) achieved clinical improve-

ment of 90% or greater (ie, excellent improvement or cleared)

with either strength of the active medication, compared with

vehicle. Improvements were achieved early in treatment and

maintained throughout the study.

In a pooled analysis of two 12-week, randomized, double-

blind studies of adult patients with moderate to severe atopic

dermatitis, Hanifin et al6 found that tacrolimus performed sig-

nificantly better (P<0.001) than vehicle, as measured by several

efficacy indicators. The adult studies, which had a total of 632

patients, used the same two concentrations of tacrolimus as the

aforementioned children’s study. In adults, the 0.1% concentra-

tion was found to be more effective in patients with severe

disease or more extensive body surface involvement.

A pediatric safety study of 180 children 7 to 16 years of age

by Boguniewicz et al7 tested three concentrations of tacrolimus

(0.03%, 0.1%, and 0.3%) for 22 days with a 2-week follow-up.

The study found no serious systemic adverse events; the most

common application-site events were pruritus and skin burning.

Pimecrolimus

Efficacy and safety of pimecrolimus were examined in three

6-week, randomized, double-blind trials of pediatric patients with

mild to moderate atopic dermatitis.8,9 The results of two of the

studies of children 1 to 17 years of age were combined. The pooled

results of those two trials, in which a total of 403 patients partici-

pated, will be referred to in this discussion as the children’s study.

The third study, in 186 infants 3 to 23 months of age, was similar

in design. It will be called the infants’ study.

In both the children’s and the infants’ studies, once the 6-week

phase ended, patients who had been on vehicle were allowed to

receive active medication in a 20-week, open-label extension.

The primary efficacy end point in both studies was Investigator

Global Assessment (IGA). The IGA ranks disease severity on a scale

of 0 (clear, defined as no inflammatory signs of atopic dermatitis)

to 5 (very severe, defined as erythema and papulation/infiltration

with oozing and crusting). Treatment success was defined as an IGA

score of 0 (clear) or 1 (almost clear) at day 43.

Secondary efficacy parameters for both studies included

Eczema Area and Severity Index (EASI) score and severity of pru-

ritus score. With the EASI, proportionate values are assigned to

four body regions, and each region is assessed separately for ery-

thema, infiltration/papulation, excoriation, and lichenification.

The severity of each region is assigned a score of 0 to 3, or from

none to severe. Possible total scores range from 0 (no disease any-

where on the body) to 72 (severest disease over total body surface

area). The pruritus score was assigned by the caregiver after

patient interview; numerical values ranged from 0 (no

itching/scratching) to 3 (bothersome itching/scratching that dis-

turbs sleep). Patients were evaluated at baseline and on days 8, 15,

22, 29, and 43.

The infant is shown before and after 6 weeks' therapy using pimecrolimus 0.1% for moderate atopic dermatitis.Courtesy of Prof. Dr. Roland Kaufmann, JW Goethe University Medical School,

Frankfurt, Germany.



The results seen in Figure 2 are typical of those seen in the

short-term pimecrolimus studies. This 7-month-old female had a

history of erythema and papulation on the face and neck and was

diagnosed with moderate atopic dermatitis. Her parents had been

applying emollients but were reluctant to use topical cortico-

steroids. The atopic dermatitis flares were causing sleep distur-

bance and distress to not only the infant but also the parents.

Twice-daily therapy with pimecrolimus was initiated to control

the atopic dermatitis and prevent exacerbations. Six weeks later,

the infant's skin was essentially cleared.

In the children’s study, a significantly higher proportion of

patients treated with pimecrolimus than those treated with vehi-

cle were clear or almost clear by IGA at every postbaseline visit

(P ≤0.05 for day 8 and 29 visits; P ≤0.001 for day 15, 22, and 43

visits). For the infants’ study, this was true beginning with the day

15 visit (P<0.001).9 EASI scores were also markedly lower at

every visit in both studies (Figure 3).8,9 In infants, pimecrolimus

was particularly effective in treating head and neck atopic der-

matitis. This may be due to better absorption on this part of the

body. In both the children’s and the infants’ studies, significantly

more (P<0.001) patients on pimecrolimus than on vehicle

reported no or mild pruritus at every postbaseline visit.8,9

In the children’s study, a larger proportion of patients in the

vehicle group discontinued participation in the study than did

patients on the active medication (25% of the control group, vs

11.2% of the pimecrolimus group). The reason most often given

was unsatisfactory therapeutic effect (cited by 15.4% of the con-

trol group vs 2.6% of the pimecrolimus group).8

Overall incidence of adverse events was comparable between

the active medication and vehicle groups in both the children’s

and the infants’ studies. Most adverse events were mild to moder-

ate and unrelated to treatment. Infections were representative of

typical childhood illnesses. The incidence of application-site reac-

tions was comparable between the active medication and the vehi-

cle groups.

During the 20-week, open-label extension, in which patients

on vehicle were rolled over to active medication, EASI scores

showed that (a) patients who had previously been on vehicle

quickly achieved the same degree of improvement as did those

who had been on active medication and (b) patients who had

been on pimecrolimus for 6 weeks prior were able to maintain

their level of improvement. These findings were true for both the

children’s and the infants’ studies.10

Long-Term Studies Show Calcineurin Inhibitors Appear Safe

Because tacrolimus has been available longer than pime-

crolimus, it has been studied in patients for a longer period of

time. Data on tacrolimus use by pediatric and adult patients for as

long as 36 months are available.11,12

Tacrolimus

Kang et al13 looked at the long-term safety of tacrolimus 0.1%

in 255 children 2 to 15 years of age who used the medication for

up to 12 months. Of these children, 52% had moderate and 48%

had severe atopic dermatitis. Patients were on medication an aver-

age of 279 (87%) study days (median, 338 days). At the end of 12

months, there was no increased incidence of infections or other

significant adverse events. Skin burning was the most common

Figure 3. Children and Adolescents: Pimecrolimus—Significant Improvement in EASI*

-100

-80

-60

-40

-20

0

20

40

Baseline 8 15 22 29 43

Children/adolescents PIMInfants PIMChildren/adolescents vehicleInfants vehicle

Median % Change From Baseline EASI Score

*Based on mean change from baseline, Cochran-Mantel-Haenszel test.Ho V, et al. Poster, annual meeting of the American Academy of Dermatology, New Orleans, La. Feb. 22-27, 2000

PIM = pimecrolimusDay

Med

ian

% C

hang

e



application-site reaction (25.9%), followed by pruritus (23.1%).

These adverse events were highest on the first few days of treatment

and typically declined after days 5 to 8 in most patients. (It has

been this author’s experience that risk of skin burning can be less-

ened by instructing the family not to apply tacrolimus to the child

immediately after bathing.)

The Kang study also looked at several efficacy measures: EASI

score decreased from 19.7 at baseline to 5.7 at month 12, percent

of body surface area affected improved, and pruritus also

decreased.

Paller et al11 evaluated long-term safety of

tacrolimus in 389 pediatric patients in a

noncomparative, open-label extension

study of patients 2 to 15 years of age. Most

patients had moderate to severe atopic der-

matitis at baseline. Mean body surface area

affected was 33%. Patients applied the

0.1% tacrolimus ointment twice daily until

1 week after clearing, with instructions to

resume treatment if atopic dermatitis

recurred. After month 3, patients were eval-

uated at 3-month intervals. Of the 389

patients, 234 had been followed for 2 years and 56 patients for 3

years.

As with the Kang study, the most common drug-related

adverse event was skin burning (18%), followed by pruritus

(15%) and erythema (5%). These events typically were of short

duration and subsided after a few days’ treatment. Incidence of

infections from herpes simplex virus (HSV) was 1.8% in the first

6 months of the study; no cases of HSV infection were reported

in months 25 to 30 (representing 131 patients). The authors

indicated that this rate was comparable to that seen in pediatric

patients with atopic dermatitis.

In a similarly designed safety study of 407 patients 16 years of

age or older, tacrolimus was found to be safe after up to 3 years

of use.12 Most patients had moderate to severe atopic dermatitis

at baseline. Nearly half of the patients were followed for at least

2 years. Skin burning, pruritus, and erythema were the most

common application-site events. The authors concluded that

long-term tacrolimus use did not increase risk of any adverse

event, including the risk associated with concurrent illnesses.

Pimecrolimus

Three long-term studies of pimecrolimus have compared the

agent’s efficacy and safety to that of conventional therapy.14,15,16

Two were 1-year studies of pediatric patients and one was a

6-month study of adults.

All three studies were similar in design: Patients were random-

ized into two groups. Both groups were instructed to apply

emollients to dry skin. At the first sign of early atopic dermatitis

symptoms, patients applied either pimecrolimus or, if they were

in the conventional therapy group, vehicle to the affected areas.

If flares occurred, patients in both groups were given moderately

potent corticosteroids to apply. All severities of atopic dermatitis,

from mild to very severe, were allowed.

In a study of 251 infants 3 to 23 months of age, pimecrolimus

significantly reduced (P<0.001) the incidence of flares compared

with the conventional therapy regimen.14 Overall corticosteroid

use was substantially lower in the pimecrolimus group; 64% used

no corticosteroids during the 12-month period, vs only 35% of

the control group. Results of a study of 713 patients 2 to 17 years

of age were similar; 57% of the pimecrolimus group did not use

any topical corticosteroid therapy, vs only 32% of the conven-

tional therapy group after 12 months.15 EASI scores in both

pediatric studies demonstrate that pime-

crolimus could maintain disease control for

1 year.15

The adult study of 192 patients 18 to 68

years of age lasted only 6 months, but

results mirrored those of the pediatric stud-

ies; pimecrolimus was found to be topical

corticosteroid–sparing. The adult study

also looked at quality of life as a secondary

efficacy indicator. Pimecrolimus was found

to significantly improve (P<0.05) quality of

life, compared with conventional therapy.16

Overall incidence of adverse effects was

comparable between the pimecrolimus and conventional therapy

groups in all three long-term studies. In the pediatric studies,

most adverse events were mild or moderate and representative of

typical childhood illnesses or atopic diseases. Application-site

reactions were low in both those who received active medication

and those who used the vehicle. There were no significant differ-

ences between the two groups.

In the children’s study by Wahn et al15, a skin-recall antigen test

was performed at the end of 12 months to see if pimecrolimus

impaired immune response to common antigens. There were no

significant differences between the two treatment groups, however.

In summary, safety and efficacy conclusions that can be

reached from clinical trials are that pimecrolimus:

• Significantly reduced signs and symptoms of eczema.

• Significantly reduced pruritus, perhaps the most vexing

symptom for patients.

• Reduced the number of flares and the need for cortico-

steroids, when used at the earliest onset of signs and

symptoms of atopic dermatitis.

• Was effective in a broad population of patients by age and

disease severity.

• Was safe for at least 1 year.

• Was safe for use over a large percentage of body surface area.

• Was safe for use on face, neck, and skinfolds, where potent

corticosteroids are contraindicated.

• Exhibited no contact sensitization, phototoxicity, photo-

allergy, or cumulative irritation.

• Showed low systemic absorption regardless of patient age,

disease extent or severity, or treatment duration.

ConclusionHave topical immunomodulators changed pediatricians’ abili-

“Overall incidence of adverse effectswas comparable

between the pimecrolimus and

conventional therapygroups in all threelong-term studies.”



ty to treat atopic dermatitis? It is the opinion of this author that

they have. These agents have been shown to be selective for the

aberrant immunologic activities that initiate and sustain atopic

dermatitis. Early treatment at the initial signs and symptoms of

atopic dermatitis improves disease control. The pimecrolimus

research, in particular, which pitted an immunomodulator

against conventional therapy, suggests that treatment should per-

haps evolve in the way management of asthma has—by starting

antiinflammatory treatment early, rather than as reactive, crisis-

based therapy, and by developing disease severity-based algo-

rithms with an emphasis on asymptomatic/disease-free periods.

References1. Meingassner JG, Di Padova F, Hiestand P, et al. Pimecrolimus (SDZ

ASM 981): Highly effective in models of skin inflammation but low

activity in models of immunosuppression. Poster presented at the

60th Annual Meeting of the American Academy of Dermatology;

February 22-27, 2002; New Orleans, La.

2. Bilich A, Aschauer H, Stuetz A. Pimecrolimus (SDZ ASM 981) is

more lipophilic and permeates less through skin than tacrolimus (FK

506). Poster presented at the 20th World Congress of Dermatology;

July 1-5, 2002; Paris, France.

3. Data on file, Novartis Pharmaceuticals Corp., East Hanover, N.J.

4. Data on file, Novartis Pharmaceuticals Corp., East Hanover, N.J.

5. Paller A, Eichenfield LF, Leung DYM, Stewart D, Appell M. A 12-

week study of tacrolimus ointment for the treatment of atopic der-

matitis in pediatric patients. J Am Acad Dermatol. 2001;44:S47-S57.

6. Hanifin JM, Ling MR, Langley R, Breneman, Rafal E. Tacrolimus

ointment for the treatment of atopic dermatitis in adult patients: Part

I, efficacy. J Am Acad Dermatol. 2001;44:S28-S38.

7. Boguniewicz M, Fiedler VC, Ramer S, et al. A randomized, vehicle-

controlled trial of tacrolimus ointment for treatment of atopic der-

matitis in children. J Allergy Clin Immunol. 1998;102:637-644.

8. Eichenfield LF, Lucky AW, Boguniewicz M, et al. Safety and effica-

cy of pimecrolimus (ASM 981) cream 1% in the treatment of mild

and moderate atopic dermatitis in children and adolescents. J Am

Acad Dermatol. 2002;46:495-504.

9. Ho V, Papp K, Halbert A, et al. Pimecrolimus (ASM 981) cream is

effective and safe in infants aged 3-23 months with atopic dermati-

tis. Poster presented at the 60th Annual Meeting of the American

Academy of Dermatology; February 22-27, 2002; New Orleans,

La.

10. Ling M, Boguniewicz M, Eichenfield LF, et al. Pimecrolimus (ASM

981) cream is safe in the long-term control of atopic dermatitis.

Poster presented at the 60th Annual Meeting of the American

Academy of Dermatology; February 22-27, 2002; New Orleans, La.

11. Paller AS, Hanifin J, Eichenfield L, Rico MJ, Ayers M. Long-term

safety of topically applied tacrolimus ointment in pediatric patients

2-15 years of age with atopic dermatitis. Poster presented at the

60th Annual Meeting of the American Academy of Dermatology;

February 22-27, 2002; New Orleans, La.

12. Caro I, Gordon KB, West DP, et al. Long-term safety of topically

applied tacrolimus ointment in adult patients with atopic dermati-

tis. Poster presented at the 60th Annual Meeting of the American

Academy of Dermatology; February 22-27, 2002; New Orleans,

La.

13. Kang S, Lucky AW, Pariser D, Lawrence I, Hanifin JM. Long-term

safety and efficacy of tacrolimus ointment for the treatment of

atopic dermatitis in children. J Am Acad Dermatol. 2001;44:S58-

S64.

14. Kapp A, Papp K, Bingham A, et al. Long-term management of atopic

dermatitis in infants with topical pimecrolimus, a nonsteroid anti-

inflammatory drug. J Allergy Clin Immunol. 2002;110:277-284.

15. Wahn U, Bos JD, Goodfield M, et al. Efficacy and safety of pime-

crolimus cream in the long-term management of atopic dermatitis

in children. Pediatrics. 2002;110(1 pt 1):e2.

16. Meurer M, Fölster-Holst R, Bräutigam M. Pimecrolimus (ASM

981) cream improves disease control and quality of life in the long-

term management of atopic dermatitis in adults. Poster presented at

the 20th World Congress of Dermatology; July 1-5, 2002; Paris,

France.

characterized by severe pruritus and morphologic features (ery-

thema, papulation, excoriation, and lichenification) that make

clinical diagnosis possible. Formal diagnostic criteria exist to

aid the clinician, but generally the diagnosis is made readily

by simple examination and history. The physician should

recognize that the disease presents differently in an infant

or child than it does in an adolescent or adult. Morphologic

features, disease duration and distribution, family history,

and other factors can be used to distinguish atopic dermatitis

from other dermatoses, including seborrheic dermatitis,

allergic contact dermatitis, scabies, and psoriasis.

CLINICAL PRESENTATIONContinued from page 6.

References1. Sicherer SH, Sampson HA. Food hypersensitivity and atopic der-

matitis: Pathophysiology, epidemiology, diagnosis, and management.J Allergy Clin Immunol. 1991;104:S114-S122.

2. Hurwitz S. Clinical Pediatric Dermatology. Philadelpha, Pa: WBSaunders Co; 1981:44-45.

3. Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. ActaDerm Venereol (Stockh). 1980;92(suppl):44-47.

4. Hanifin JM. Immunologic aspects of atopic dermatitis. DermatolClin. 1990;8:747-750.

5. Shin HT, Chang MW. Drug eruptions in children. Curr Probl Pediatr.2001;31:207-234.


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Pediatric News®

ATOPIC DERMATITIS IN THE PEDIATRIC PATIENT: PATHOPHYSIOLOGY, PRESENTATION, AND AN UPDATE ON NOVEL THERAPIES

CME Post-Test and Evaluation

Copyright 2003 International Medical News Group, an Elsevier Science company

INSTRUCTIONS: For each question or incomplete statement, one answer is correct. Check the most appropriate response. Seven out of ten correct responses are required for credit.

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PROGRAM EVALUATION1. How many hours did you actually spend completing this activity?

0.5 to 1 hour 1 to 1.5 hours 1.5 to 2 hours 2 to 2.5 hours

2. Rate how well the activity achieved the learning objectives listed on page 3.

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3. Rate the relevance of the activity’s content to its objectives.

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4. Rate the faculty’s effectiveness in communicating the material.

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5. Rate the information about diagnosis and treatment of atopic dermatitis in pediatric

patients.

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6. This supplement was commercially supported. Did you perceive any bias?

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If yes, please explain.

7. How would you rate the content? (Circle the letter of the most appropriate answer.)

a. Will definitely change the way I practice

b. Challenged me to think about the topics

c. Applicable to my practice—a good review

d. Of limited use in my practice

e. Not applicable to my practice

8. What other CME topics would be of value to you? Please offer additional comments.

1. Approximately ____ of all cases of atopic dermatitis are diagnosed by 5years of age.a. 60% c. 80%b. 70% d. 90%

2. Which of the following statements about atopic dermatitis is true?a. Atopic dermatitis can cause failure to thrive.b. Atopic dermatitis remits in a minority of children by the time they

reach puberty.c. T-helper type 2 cells are associated with chronic atopic dermatitis.d. Because Staphylococcus aureus is so prevalent in atopic dermatitis lesions,

antibiotics should be used only in cases of overt infection.

3. Which of the following side effects is not associated with corticosteroid use?a. Telangiectasiab. Glaucomac. Skin atrophyd. Rapidly increasing response to the medication after several weeks’ use

4. Which of the following is not an effective treatment for atopic dermatitis?a. Oral antihistamines c. Topical immunomodulatorsb. Topical antihistamines d. Avoidance of known triggers

5. Which of the following morphologic features is not commonly associated with atopic dermatitis?a. Erythema c. Excoriationb. Hemorrhagic erosions d. Lichenification

6. Pruritus and papulation accompanied by small linear burrows and noduleson the wrists, ankles, and finger webs in an older child are likely signs of:a. Nummular dermatitis. c. Eczema herpeticum.b. Molluscum contagiosum. d. Scabies.

7. Young infants are more likely than older children to have atopic dermati-tis:a. On the hands. b. In the diaper region.c. On the cheeks.d. None of the above.

8. Which of the following statements comparing tacrolimus and pimecrolimus is true?a. In immunosuppression models, pimecrolimus has been found to have

a higher potential for affecting systemic immune responses.b. Tacrolimus is more lipophilic than pimecrolimus.c. Pimecrolimus was equal or superior to tacrolimus in skin

inflammation models.d. All of the above statements are true.

9. Which statement is accurate regarding the findings of the two short-term pimecrolimus efficacy trials in infants and children?a. A significantly higher proportion of patients treated with

pimecrolimus than vehicle were rated clear or almost clear byInvestigator Global Assessment at the day 15 visit.

b. Pruritus relief was not seen in most patients on active medication untilthe day 29 visit.

c. Patients on pimecrolimus had significantly more application-site reac-tions than did patients on vehicle.

d. The 20-week extension phase of the trials showed that tachyphylaxis may be an issue with pimecrolimus after week 14.

10. Long-term safety trials that measured the effectiveness of pimecrolimus vs that of conventional therapy found pimecrolimus: a. To be topical corticosteroid-sparing.b. Could maintain disease control for up to 1 year.c. Did not impair immune response to common antigens.d. All of the above are true.

A


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