Ebook Textbook of aging skin: Part 2

(BQ) Part 2 book Textbook of aging skin presents the following contents: Biomarkers, in vitro techniques, pigmentation, diseases associated with aging, malignant skin conditions, on malignant skin conditions, bioengineering methods and tools, percutaneous penetration,...

46 Tobacco Smoke and Skin Aging*

Akimichi Morita

Introduction

has a deleterious effect on the skin, and smoker’s wrinkles

are the typical clinical features of smokers A recent

epi-demiological study has clearly shown that tobacco

smok-ing is one of the numerous factors contributsmok-ing to

premature skin aging, which is dependent on age, sex,

pigmentation, sun exposure history, alcohol

study, sun exposure, pack years of smoking history, and

potential confounding variables were assessed by

ques-tionnaire Facial wrinkles were quantified using the

Daniell score Logistic statistical analysis of the data

revealed that age, pack year, and sun exposure

this survey, age (OR = 7.5, 95% CI = 1.87 30.16), pack

year (OR = 5.8, 95% CI = 1.72 19.87), and sun exposure

(OR = 2.65, 95% CI = 1.0 7.0) independently

contrib-uted to the formation of facial wrinkles, as estimated by a

logistic regression analysis model Using silicone rubber

replicas combined with computerized image processing,

an objective measurement of skin’s topography, the

asso-ciation between wrinkle formation and tobacco smoking

was investigated Sixty-three volunteers were enrolled by

assessing their skin replicas, in an attempt to elucidate the

The replica analysis showed that the depth (Rz) and

variance (Rv) of furrows (Rv) in subjects with smoking

subjects with smoking history were significantly lower

Tobacco smoking, which is regarded as an important

environmental factor, can potentially cause ‘‘tobacco

ultra-violet (UV) radiation results in marked alterations in

the structure and composition of the epidermis and

smoking per se or smoking combined with UV exposure

Molecular Mechanisms of Induced Skin Aging

Tobacco-Tobacco smoking probably exerts its deleterious effects onskin directly through its irritant components on the epi-dermis and indirectly on the dermis via the blood circula-

the face contributes to facial wrinkling because of thedirect toxicity of the smoke Pursing the lips duringsmoking with contraction of facial muscles and squintingbecause of the irritating of smoke may cause the forma-tion of wrinkling around the mouth and in the crow’s foot

metabolism have been brought into focus as a major

demonstrated that accumulation of elastosis material isaccompanied by the degradation of matrix protein, which

is mediated by matrix metalloproteinases (MMPs) inskin aging The molecular alteration in the dermisincludes the decrease of collagen synthesis, induction

of MMPs, abnormal accumulation of elastic fibers, and

of both procollagen types I and III, the precursors ofcollagen, were significantly decreased from the superna-tant of cultured fibroblast treated with tobacco smoke

∗ Originally published as Tobacco Smoke and Skin Aging in Halliwell, B.B., Poulsen, H.E (eds.), Cigarette Smoke and Oxidative Stress, Heidelberg, Springer, 2006 pp 379–385 Reprinted with permission.

M A Farage, K W Miller, H I Maibach (eds.), Textbook of Aging Skin, DOI 10.1007/978-3-540-89656-2_46,

# Springer-Verlag Berlin Heidelberg 2010

indicated that the final production of collagen secreted

into the medium is reduced, regardless of the rate of

collagen synthesis in the cell tested in 3H-proline

incorporation

Although elastic fibers account for only 2–4% of

ex-tracellular matrix, these provide elasticity and resilience to

normal skin Tobacco smoke extracts induced the

signifi-cant increase in tropoelastin mRNA in cultured skin

fibro-blasts Accumulation of abnormal elastic material (termed

solar elastosis) is the prominent histopathologic alterations

tobacco smoking could facilitate smoke’s elastosis of the

subjects with an average of 42 pack years of tobacco

smoking In an in vitro study using cultured skin

fibro-blasts, tobacco smoke extracts induced elevation of

tro-poelastin This might be attributed to premature skin

aging

The expressions of MMP-1 and MMP-3 mRNA,

extracellular matrix (ECM)-associated members of

the MMPs gene family, were induced in cultured skin

fibroblast stimulated with tobacco smoke extracts in a

concept that MMPs are primary mediators of connective

tissue damage in skin exposed to tobacco smoke extracts

and of the premature skin aging In addition, expression

inducing the expressions of MMP-1 and MMP-3, but

not the induction of tissue inhibitor of MMPs, tobacco

smoke extracts could alter their ratio in favor of the

induction of MMPs and appears to result in a more

degradative environment that produces loss of cutaneous

of degradative enzymes, which are responsible for the

degradation of extracellular matrix components such as

native collagen, elastin fibers, and various proteoglycans

MMP-3 and MMP-7 may play a key role in the

increased in fibroblasts induced by tobacco smoke extract

Effect of Tobacco Smoke In Vivo

In a clinical study, significant higher levels of MMP-1

mRNA were observed in the buttock skin of smokers,

compared with nonsmokers, using quantitative real-time

degra-dation of collagen, elastic fibers, and proteoglycans

Therefore, the observations in dermal connective tissue

induced by the treatments of tobacco suggested an

imbal-ance between the biosynthesis and degradation, with less

repair capacity on the face of the ongoing degradation,

which leads to the loss of collagen and elastic fibers,manifesting clinically as aging appearance of skin.Although staining of skin specimen and biochemicalanalysis of photodamaged skin demonstrated increased gly-cosaminoglycan content of sun-damaged skin, the under-lying molecular pathogenesis remains unclear Versican,the large chondroitin sulfate (CS) proteoglycan, has beenidentified in the dermis in association with elastic fibers,which contain a hyaluronic acid-binding domain Thecore protein has been postulated to play a role in molecularinteractions and specifically, to facilitate the binding of thesemacromolecules to other matrix components or cytokines

small CS proteoglycan, has been shown to codistributewith collagen fibers and postulated to function in cellrecognition, possible by connecting extracellular matrix

disruption of decorin synthesis in mice resulted in a

There was a decrease in the proportion of large CS teoglycan (versican) and a concomitant increase in theproportion of small dermatan sulfate proteoglycan (dec-orin) as a function of age as reported by Carrino et al

strongly in young rats and faintly in old rats On the otherhand, decorin was faintly stained in the young rats anddistinctly stained in the old rats There were severalreports concerning the changes of proteoglycans on pho-

of new synthesized proteoglycans showed a marked

decorin immunostaining increased in photoaged tissuesamples, accompanied by similar alterations in gene ex-

versican protein and mRNA levels in cultured akin blasts However, tobacco smoke extract exposure resulted

fibro-in a significant fibro-increase of decorfibro-in These results aresimilar to those observed in photoaging

Based on experimental evidence, a working model forUVA damage skin was proposed, in which UV irradiationgene expression was mediated via the generation of singletoxygen through a pathway involving activation of tran-

the reactive oxygen species (ROS) were involved in gulation of MMPs induced by tobacco, sodium azide(NaN3), l-ascorbic acid, and vitamin E, which are potentquenchers of singlet oxygen and other ROS, were emp-loyed NaN3, l-ascorbic acid, and vitamin E abrogatedthe induction of MMPs after exposure of fibroblast totobacco smoke extract Among the antioxidant reagents,l-ascorbic acid most obviously diminished the increase in

upre-448 46 Tobacco Smoke and Skin Aging

MMP-1 expression level on exposure of fibroblasts to

ROS were most probably responsible for the enhanced

induction of MMPs by tobacco smoke extract

The TGF-b1 is a multifunctional cytokine that

regu-lates cell proliferation and differentiation, tissue

in the epidermis, playing an important role in the

main-tenance of tissue homeostasis In the dermis, however,

TGF-b1 acts as a positive growth factor, inducing the

synthesis of extracellular matrix proteins TGF-b signals

through a heteromeric complex of type I/II TGF-b

showed that UV irradiation can cause downregulation

of TGF-b type II receptor mRNA and protein, and

Tobacco smoke extracts induced the latent form TGF-b,

not the active form, assayed by enzyme-linked

immuno-sorbent assay (ELISA), in the supernatants of cultured skin

from tobacco-exposed cells contributes to the

intracellu-lar defense capacity Fibroblasts responses to TGF-b1 are

mediated through its active form binding to the cell

surface receptor Tobacco smoke extracts blocked cellular

responsiveness to TGF-b1 through the induction of

non-functional latent form and downregulation of TGF-b1

useful to stimulate the collagen production or to protect

against the deleterious effects of tobacco smoke

Conclusion

Tobacco smoke contains numerous compounds, with at

contributed to the damage of connective tissue is still

unclear The tobacco-induced skin aging provides a tool

for studying the effects of smoking Also, detailed

knowl-edge may provide a motivation to stop smoking,

espe-cially among those who are more concerned about their

appearances than the potential internal damage

asso-ciated with smoking

References

1 Daniell HW Smoker’s wrinkles: A study in the epidemiology of

‘‘crow’s feet Ann Intern Med 1971;75:873–880.

2 Ernster VL, Grady D, Miike R, et al Facial wrinkling in men and

women, by smoking status Am J Public Health 1995;85:78–82.

3 Frances C Smoker’s wrinkles: epidemiological and pathogenic

con-siderations Clin Dermatol 1998;16:565–570.

4 Grady D, Ernster V Does cigarette smoking make you ugly and old?

7 Yin L, Morita A, Tsuji T Skin premature aging induced by tobacco smoking: The objective evidence of skin replica analysis J Dermatol Sci 2001b;27(Suppl 1):S26–S31.

8 Yin L, Morita A, Tsuji T Tobacco smoking: a role of premature skin aging Nagoya Med J 2000;43:165–171.

9 Fisher GJ, Talwar HS, Lin J, et al Molecular mechanisms of aging in human skin in vivo and their prevention by all-trans- retinoic acid Photochem Photobiol 1999;69:154–157.

photo-10 Grether-Beck S, Buettner R, Krutmann J Ultraviolet A induced expression of human genes: Molecular and photobiological mechanisms Biol Chem 1997;378:1231–1236.

radiation-11 Wenk J, Brenneisen P, Meewes C, et al UV-induced oxidative stress and photoaging Curr Probl Dermatol 2001;29:83–94.

12 Leung W-C, Harvey I Is skin ageing in the elderly caused by sun exposure or smoking? Br J Dermatol 2002;147:1187–1191.

13 Lofroth G Environmental tobacco smoke: overview of chemical composition and genotoxic components Mutat Res 1989;222:73–80.

14 Smith JB, Fenske NA Cutaneous manifestations and consequences

of smoking J Am Acad Dermatol 1996;34:717–732.

15 Uitto J, Fazio MJ, Olsen DR Molecular mechanisms of cutaneous aging: Age-associated connective tissue alterations in the dermis.

J Am Acad Dermatol 1989;21:614–622.

16 Fisher GJ, Voorhees JJ Molecular mechanisms of photoaging and its prevention by retinoic acid: ultraviolet irradiation induces MAP kinase signal transduction cascades that induce Ap-1-regulated matrix metalloproteinases that degrade human skin in vivo J Inves- tig Dermatol Symp Proc 1998;3:61–68.

17 Shuster S Smoking and wrinkling of the skin Lancet 2001;358:330.

18 Yin L, Morita A, Tsuji T Alterations of extracelluar matrix induced by tobacco smoke extract Arch Dermatol Res 2006;292: 188–194.

19 Montagna W, Kirchner S, Carlisle K Histology of sun-damaged human skin J Am Acad Dermatol 1989;21:907–918.

20 Tsuji T Ultrastucture of deep wrinkles in the elderly J Cutan Pathol 1987;14:158–164.

21 Boyd AS, Stasko T, King LE Jr., et al Cigarette smoking-associated elastotic changes in the skin J Am Acad Dermatol 1999;41:23–26.

22 Saarialho-Kere U, Kerkela E, Jeskanen L, et al Accumulation of matrilysin (MMP-7) and macrophage metalloelastase (MMP-12) in actinic damage J Invest Dermatol 1999;113:664–672.

23 Lahmann C, Bergemann J, Harrison G, et al Matrix tease-1 and skin ageing in smokers Lancet 2001;357:935–936.

metallopro-24 Fisher LW, Termine JD, Young MF Deduced protein sequence of bone small proteoglycan I (biglycan) shows homology with proteo- glycan II (decorin) and several nonconnective tissue proteins in a variety of species J Biol Chem 1989;264:4571–4576.

25 Zimmermann DR, Ruoslahti E Multiple domains of the large blast proteoglycan, versican EMBO J 1989;8:2975–2981.

fibro-26 Danielson KG, Baribault H, Homes DF, et al Targeted disruption of decorin leads to abnormal collagen fibril morphology and skin fragility J Cell Biol 1997;136:729–743.

27 Carrino DA, Sorrell JM, Caplan AI Age-related changes in the teoglycans of human skin Arch Biochem Biophys 2000;373:91–101.

pro-Tobacco Smoke and Skin Aging 46 449

28 Ito Y, Takeuchi J, Yamamoto K, et al Age differences in

immunohis-tochemical localizations of large proteoglycan, PG-M/versican, and

small proteoglycan, decorin, in the dermis of rats Exp Anim.

2001;50:159–166.

29 Bernstein EF, Fisher LW, Li K, et al Differential expression of the

versican and decorin genes in photoaged and sun-protected skin:

Comparison by immunohistochemical and northern analyses Lab

Invest 1995;72:662–669.

30 Margelin D, Fourtanier A, Thevenin T, et al Alterations of

proteo-glycans in ultraviolet-irradiated skin Photochem Photobiol 1993;

58:211–218.

31 Massague J TGF-beta signal transduction Annu Rev Biochem.

1998;67:753–791.

32 Kadin ME, Cavaille-Coll MW, Gertz R, et al Loss of receptors for

transforming growth factor beta in human T-cell malignancies Proc

Natl Acad Sci USA 1994;91:6002–6006.

33 Piek E, Heldin CH, Ten Dijke P Specificity, diversity, and regulation in TGF-beta superfamily signaling FASEB J 1999;13: 2105–2124.

34 Quan T, He T, Voorhees JJ, et al Ultraviolet irradiation blocks cellular responses to transforming growth factor-beta by down-regulating its type-II receptor and inducing Smad J Biol Chem 2001;276: 26349–26356.

35 Yin L, Morita A, Tsuji T Tobacco smoke extract induces age-related changes due to the modulation of TGF-b Exp Dermatol 2003;12: 51–56.

36 Bartsch H, Malaveille C, Friesen M, et al Black (air-cured) and blond (flue-cured) tobacco cancer risk IV: molecular dosimetry studies implicate aromatic amines as bladder carcinogens Eur J Cancer 1993;29A:1199–1207.

450 46 Tobacco Smoke and Skin Aging

25 Unique Skin Immunology of the

Lower Female Genital Tract with Age

Paul R Summers

Introduction

It has been long recognized that the genital tract must

be able to defend against significant microbial exposures

In this area of medicine, old theories that may have even

acquired some attributes of folklore must be revised

to include new knowledge Through the last century,

popular ideas regarding mechanisms of microbial

defenses in the genital tract have reflected the medical

thinking of each era In the time of antisepsis of the

early twentieth century, lactic acid from the lactobacillus

was proposed as the chief regulatory vaginal antiseptic

Subsequently, the possibility of antiseptic action from

hydrogen peroxide-producing lactobacilli was considered,

although little hydrogen peroxide would be expected to be

produced in the naturally anaerobic environment of the

vaginal lumen With the influence of the more recent

antibiotic era, research interest has focused upon

bacter-iocins, unique but relatively weak lactobacillus-derived

antibiotics Theories of microbial defense have evolved

further in the current, more enlightened era of

immuno-logy Rapid advances in the area of immunology have now

disclosed complex immune defenses in the genital

epithe-lium that do have a significant antimicrobial impact,

moderated by estrogen

From the immune standpoint, the lower genital tract

has the following competing roles: (1) to facilitate the

various aspects of reproduction and (2) to simultaneously

prevent the access of locally resident microbes to the upper

genital tract and to the peritoneal cavity To facilitate a

primary function in reproduction, the immune

responsive-ness of the lower female genital tract is blunted Ovulation,

fertilization, pregnancy, labor, and delivery of the infant are

all mediated by immune mechanisms that may not be

optimal for microbial defense A blunted humoral immune

response may be compensated by an active innate or

cell-mediated response For example, sperm may be highly

immunogenic If sperm are detected by the humoral

im-mune system, the development of antisperm antibodies

immune system to identify potential pathogens, but not

to target sperm or the fetus, or to disrupt the immunemechanisms of fertility

Microbial and immune events in the female urethra

function and microbial flora of the vaginal vestibule andurethra change in a parallel fashion in response to theeffects of aging and hormone cycles Hormone changesalter the morphology and mucosal defenses Menopausaldecline in innate immune defenses in the vaginal mucosaallows colonization with potential uropathogens andincreases the risk for bladder infection

Humoral ImmunityThe humoral immune system associated with vaginalmucosa is unique Mucosal surfaces outside the genitaltract develop in conjunction with lymphoid tissue thatpredominantly produces IgA At other body sites, IgAmay have a significant role in mucosal defense againstmicrobes With the absence of associated lymphoid tissue,vaginal mucosa releases only limited quantities of anycategory of immunoglobulin at all stages of life IgG ispresent in vaginal secretions The relatively small amount

of IgG is serum-derived as well as locally produced in the

of a local source of IgA, more IgG than IgA is detected in

surfaces elsewhere in the body

Cervical secretions have a higher concentration of IgA

the presumed protective role of cervical mucus to preventascent of microbes into the endometrial cavity The con-centration of IgA in vaginal secretions declines by 90% afterhysterectomy so the upper genital tract may be assumed to

be the primary source of the small quantity of IgA that is

a similar decline in lower genital tract immunoglobulinsafter the menopause, with the minimal production ofcervical mucus and vaginal secretions at that time in life.Cervical secretion of IgG and IgA into the vaginal pool

M A Farage, K W Miller, H I Maibach (eds.), Textbook of Aging Skin, DOI 10.1007/978-3-540-89656-2_25,

# Springer-Verlag Berlin Heidelberg 2010

varies during the menstrual cycle with the highest levels

prior to ovulation during the proliferative phase, but with

amount of immunoglobulin in vaginal secretions may

lower the risk for the development of antisperm

antibo-dies It is reasonable to speculate that sperm survival may

be enhanced in some fashion by the further decline in

immunoglobulins around the time of ovulation

Disruption of vaginal immunoglobulin homeostasis

can be harmful Electrical loop excision of the cervical

transformation zone (LEEP) may allow an unregulated

humoral immune response at that site Serum antisperm

antibodies have been identified in women who are

Innate Immunity

The innate immune system has major importance in

preventing invasion of potentially pathogenic microbes

normally found in the lower genital tract and on the

perirectal skin During the reproductive years, an active

innate immune response compensates somewhat for the

blunted humoral and cell-mediated immune response in

transmitted diseases develop when sexually acquired

pathogens have the ability to evade these standing

secretory leukocyte protease inhibitor (SLPI), elafin, and

mannose binding lectin (MBL) have been demonstrated

SLPI is in the cervical mucus plug, although it is expressed

in secretions throughout the female genital tract SLPI

blocks the action of various destructive enzymes that

may be released by pathogens Elafin is an important

protein that inhibits inflammation-related tissue damage

by blocking elastase, which may be released by activated

neutrophils Elafin also has antimicrobial activity

Leuko-cytes and vaginal epithelial cells are the main sources of

are active against various bacteria and yeast Surfactantproteins in vaginal mucosal secretions (SP-A, SP-D) pro-tect against viral infections, including HIV-1 and herpes

These secretory products of the innate immune system areconsidered to be estrogen dependent, since many are theresult of local mucosal metabolism, and the secretory fluidthat contains these substances requires estrogen stimu-lation Menopause results in a decline in the mucosal-dependent elements of the innate immune system.Minor congenital defects in the innate immune system,such as polymorphisms which result in deficiency of man-nose binding lectin (MBL), increase the risk of symptomatic

activation by binding to the cell surface of pathogenicmicrobes MBL is produced mainly in the liver and mostlikely arrives in the vaginal secretions as a transudate fromthe blood stream MBL is a significant factor in vaginalmucosal defense against pathogens, although the MBLlevel in vaginal secretions is much lower than the levelnormally found in the systemic circulation It is not clearwhether MBL is produced by vaginal mucosal cells.During the reproductive years, toll-like receptors (TLRs)

1, 2, 3, 5, and 6 are expressed in vaginal mucosal cells TLR

1, 2, and 5 mainly target bacteria TLR 3 is directed against

is estrogen-dependent This may explain the pre-pubertaland possibly post menopausal increased mucosal suscep-tibility to pathogens such as streptococcus or Neisseriagonorrhea

Cell-Mediated ImmunityLangerhans cells are abundant in vaginal and cervical mu-

Langerhans cells are most prevalent in the normal cervicaltransformation zone, so the cervical transformation zone

is assumed to be the major site for cell-mediated immune

immune consequences of excision of this important area

by extensive LEEP or cervical cone biopsy have not been

consid-ered to be a major immune organ, then the cervix should

be considered to have special immune function in thatorgan Chronic cervicitis, often detected on cervical biop-

sy in asymptomatic women is actually a misnomer, asthe normal cervical transformation zone is a site of signif-icant immune activity in normal health Pathogenic

Table 25.1

Important characteristics of the cervical transformation

zone during the reproductive years

High concentration of elements of cell-mediated immunity

to interact with viruses and to prevent ascent of bacteria

into the upper genital tract and peritoneum

Macrophages are involved in cervical ripening prior to labor

Macrophages and granulocytes are involved in cervical

dilation during labor

254 25 Unique Skin Immunology of the Lower Female Genital Tract with Age

microbes can activate cervical inflammation, but the

pres-ence of numerous immune cells is actually physiologic

The increased vulnerability of the relatively fragile

transi-tional epithelium in the transformation zone may require

better standing defenses to prevent ascending infection

During the reproductive years, and to a greater extent

during pregnancy, estrogen down-regulates antigen

pre-senting cells This results in a shift toward a Th2 immune

specific reference to the female lower genital tract, a Th2

response down-regulates the defensins and other secretory

immune compromise is presumed to be important for

normal fertility and pregnancy However, there are

conse-quences, such as an increased risk for allergic contact

der-matitis, as well as increased susceptibility to yeast, viruses,

and other pathogens Sexually transmitted diseases typically

The abundant macrophages and granulocytes in the

cervical transformation zone are regulated by hormone

changes of pregnancy Reflecting the immune suppression

of pregnancy, the number of macrophages in the cervical

transformation zone declines in early pregnancy, and then

increases in preparation for labor Macrophages are

involved in cervical ripening just prior to the onset of

labor, and macrophages and granulocytes have a

Immune Changes with Age

Innate immune defenses of the vaginal mucosa are

com-promised with aging Estrogen influences the expression

colonization with pathogens The post menopausal lack of

epithelial cell maturation results in loss of vaginal surface

barrier function Pathogens can invade the more readily

traumatized fragile epithelium Estrogen deficiency leads

to a decline in mucosal secretions that contain the

anti-microbial constituents of the innate immune system

The neutral vaginal pH after the menopause reflects loss

of the acid defense as well as a significant decline in

vaginal mucosal metabolic ability

Cell-mediated immunity is estrogen and age

depen-dent Langerhans cells are most prevalent in vulvar skin

on dendritic cells moderate the maturation of functional

in Langerhans cell function with aging, as well as a

A decreased response to cytokines is also characteristic

trans-formation zone is gradually eliminated by the agingprocess of squamous metaplasia

Antigen presenting cells are still present in the vaginal

replacement can reactivate deficient vaginal mucosal mediated immune function Asthma is a good example ofthe estrogen effect upon cell-mediated immunity Asthma

cell-is influenced by the estrogen-related shift of cell-mediatedimmunity from a Th1 to a Th2 environment Asthma ismore prevalent in males than females prior to puberty, buthigher in females with the rise in estrogen after puberty

replacement therapy after menopause may make asthma

replace-ment may restore a Th2 environreplace-ment that favors vaginalcolonization with yeast

Very low IgA very low IgG IgG > IgA Cell-mediated

leuko- Table 25leuko-.3

Characteristics of the lower female genital tract in the absence of estrogen

Innate immunity Decreased expression of TLRs decrease

in all secretory products Humoral

immunity

Further decline in IgA with decreased cervical secretions

Cell-mediated immunity

Decline in langerhans cell count decline

in cytokine responsiveness associated suppression of Th1 response

estrogen-is eliminated

TLR toll like receptor; HBD human beta defensin; SLPI secretory cyte protease inhibitor; MBL mannose binding lectin; SP surfactant proteins

leuko-Unique Skin Immunology of the Lower Female Genital Tract with Age 25 255

Lower female genital tract immune defenses are complex

and are not yet completely understood Clearly, the immune

system plays a major role in regulating vaginal microflora,

but unfortunately, many pathogens have mechanisms to

evade the immune defenses Estrogen promotes the innate

system, but suppresses the cell-mediated response in the

lower genital tract Humoral immunity appears to play

only a small role in this portion of the female body Immune

function during the reproductive years reflects a balance

between the need to protect against infection and the

requirements of reproduction

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28 Yawn BP, Wollan P Kurland MJ, Scanlon P A longitudinal study of asthma prevalence in a community population of school age chil- dren J Pediatr 2002;140(5):576–581.

29 Balzano G, Fuschillo S, Melillo G, Bonini S Asthma and sex mones Allergy 2001;56(1):13–20.

hor-30 Kos-Kudla B, Ostrowska Z, Marek B, et al Effects of hormone replacement therapy on endocrine and spirometric parameters in asthmatic postmenopausal women Gynecol Endocrinol 2001;15(4): 304–311.

256 25 Unique Skin Immunology of the Lower Female Genital Tract with Age

Specialized Skin: Genital

24 Vaginal Secretions with Age

Paul R Summers

The Source of Vaginal Secretions

In the developing fetus, the vaginal epithelium is

trans-formed from columnar to squamous prior to term birth

With the exclusion of the vaginal epithelium, most

muco-sal surfaces in the human body that demonstrate this type

of squamous metaplasia during fetal development retain

specific secretory glands In spite of an absence of

secre-tory subdermal glands, it is significant that the vaginal

epithelial cells retain a remarkable secretory ability

Vaginal mucosa contains a microscopic intercellular

network of secretory pathways Intercellular channels are

found between the tight junctions in the intermediate cell

layer of the mucosa These areas of dilation start as clefts

in the parabasal cell layer of the epithelium, and appear as

pores that can be seen at the mucosal surface using

is, then, a secretory structure The mucosal secretions of

the female lower genital tract fulfill several important

roles in the process of reproduction, ranging from

lubri-cation, to microbial inhibition, to sperm facilitation

In a manner similar to mucosa at other body sites, it is

presumed that vaginal secretions trap potentially

patho-genic bacteria The constant daily drainage of

approxi-mately 2 cc of secretions may, in that case, contribute

More important, the confluent coating of secretions may

restrict pathogens from contacting the mucosal surface, to

prevent the essential first step in the establishment of

infection

The most widely recognized constituent of vaginal

mucosal secretions is the lactobacillus More recent

non-culture-based data have shown a number of acid-producing

bacteria that may be present with or instead of

of the various lactobacillus and other acid-producing

bacteria strains that are considered normal flora A mildly

acidic pH and the presence of glycogen are two key factors

for these strains Metabolically restricted to anaerobic

glycolysis, the lactobacillus strains release significant

amounts of lactic acid into the vaginal mucosal secretions

Tradition attributes a protective role for the lactobacillus

against potential pathogens, although clinical experiencesuggests this presumed defensive action of the lactobacil-lus is strikingly inadequate In spite of the essentiallyubiquitous presence of acid-producing bacteria in normalvaginal secretions, the vaginal mucosa remains susceptible

to a wide range of pathogenic microbes

During the antiseptic era of the early twentieth

centu-ry, it was presumed that the lactate content of vaginalsecretions contributed a significant antiseptic action to

view of vaginal antisepsis still remains popular, modernresearch has disclosed other constituents of vaginal secre-tions that present a more plausible explanation for anti-microbial action in the vaginal secretions

Human epithelial cells are highly active in the tion of a wide range of metabolic products In this regard,the vaginal mucosa is no exception Many of these chemicalproducts are released into the vaginal secretions, in somecases presumably to carry out a protective role More than 40different organic substances have been identified in normalvaginal secretions Lactate is the primary acid that contri-butes to the low vaginal pH, but other normal constituentsrange from 15 typical aliphatic acids (such as acetic, myr-iatic, linoleic) to alcohols, glycols, and various aromatic

elements of the innate and humoral immune systems,such as defensins and small amounts of IgA and IgG, inthe vaginal fluid (refer to the chapter on immunology ofthe female lower genital tract) Unfortunately, vaginalpathogens are often able to evade the potential immuneand mechanical barriers presented by the coating of mu-cosal secretions For example, the polymicrobial patho-gens of bacterial vaginosis produce hydrolytic enzymesthat lyse the protein base of vaginal mucosal secretions

Hormone Influence upon the Vaginal Mucosal Secretions

Hormone production regulates the quantity and ter of vaginal mucosal secretions Under the influence of

charac-M A Farage, K W Miller, H I Maibach (eds.), Textbook of Aging Skin, DOI 10.1007/978-3-540-89656-2_24,

# Springer-Verlag Berlin Heidelberg 2010

estrogen, the glycogen-rich intermediate cell layer of the

mucosa is the area of greatest metabolic and secretory

activity Basal and superficial cell regions are less

metabol-ically important Under the influence of cyclic hormone

changes, constituents of vaginal secretions change

content is greatest between 48 h prior to 24 h after the

luteinizing hormone (LH) surge Mid-cycle changes

probably reflect increased mucosal metabolic activity at

intermediate cell layer of the mucosa is lost, with a

vaginal subdermal blood flow is decreased after

pH and Vaginal Secretions

Tradition has assigned an acid pH around 4.5 to be the

main regulatory parameter for the vagina (see Chart)

Lactic acid is the major source of hydrogen ions in vaginal

common literature tends to attribute vaginal lactic acid

production solely to the lactobacillus, the vaginal mucosa

also releases lactate as an end result of glycolysis A

signif-icant amount of lactic acid is a by-product of normal

are not the only source of vaginal lactate, and actually

may not be the primary source

Lactate from Lactobacillus vs Mucosal Glycolysis

Early studies demonstrated the dual sources of vaginallactate, and even suggested mucosal glycolysis as the pri-mary source There is no direct correlation between the

pH of vaginal mucosal secretions and the presence oflactobacilli, nor is there a correlation between the amount

of glycogen substrate for growth of lactobacilli and the

significant vaginal colonization with lactobacillus, the pHmay still be in the normal acid pH range For example, anewborn has significant lactate in the initially sterile vagi-nal secretions, with a pH of around 5, prior to any colo-

estrogen influence, the vaginal pH of the infant rises to theneutral range as the metabolic activity of the vaginalmucosa declines by 6 weeks of life The vagina does notbecome colonized with lactobacillus until puberty Theneutral vaginal pH after menopause is associated with asignificant lack of lactate as a result of diminished glycol-ysis in the intermediate cell layer of the mucosa, as well as

a lack of lactobacillus In view of this early research, it issurprising that the idea that the lactobacillus is the singlesource of lactate prevails in the current commonunderstanding

Recent research also suggests that lactate from lysis in the vaginal mucosa may have the chief regulatoryrole for vaginal pH For example, pH in the vaginal

gylco- Figure 24gylco-.1

Theory of microbial inhibition proposed in the early twentieth century

248 24 Vaginal Secretions with Age

fornices has been shown to be lower than the pH in the

mid vagina, in spite of a relatively uniform distribution of

explain the observation that mucosal secretion during

sexual stimulation appears to contain the same

concen-tration of lactate that is found in the non-stimulated state

lactoba-cillus metabolism or growth, with resulting release of

excess lactate, could explain the brief decline in pH at

Estrogen directly and indirectly regulates vaginal

Microbial sources of lactate are dependent upon

estrogen-induced glycogen as an energy source Similarly, vaginal

mucosal anaerobic metabolism is estrogen-dependent

Possibly, a separate mechanism for vaginal mucosal pH

regulation has been identified Under the influence ofestrogen, superficial vaginal mucosal cells may secretehydrogen ions into the vaginal lumen in a manner similar

lactate production was not reviewed in this study, butanaerobic metabolism of glycogen remains the primesource of intracellular hydrogen ions Decreased mucosalmetabolism after menopause alters content as well asquantity of normal mucosal secretions

Either vaginal glycogen increases under the influence

increased lactate The vaginal pH fluctuates with themenstrual cycle, with its lowest average value around thetime of ovulation Presumably, this would be evidence ofmaximal anaerobic skin metabolism and lactate release

Figure 24.2

Vaginal pH and other mucosal effects of estrogen

Vaginal Secretions with Age 24 249

Sperm survive best in an anaerobic environment It is

reasonable to speculate that this enhanced anaerobic

en-vironment at the time of ovulation may contribute to

Vaginal pH with Age

The vaginal pH is not just important for microbe control,

but a mildly acid pH is also ideal for normal vaginal skin

metabolism, including the production of various proteins

that are important for vaginal immune defenses The rise

in vaginal pH after menopause results in a loss of natural

skin defenses, with an increased rate in the urinary tract

to the menopausal vagina restores a normal pH and

function is compromised by the typically neutral

meno-pausal vaginal pH This rise in pH increases the

skin pH results in defective enzyme function and vulvar

known to be essential for a normal inflammatory

concept most likely also applies to vaginal mucosa

Appli-cation of neutral pH buffers to skin in general results in

It is only reasonable to conclude that this concern also

applies to the neutral vaginal pH in the menopausal state

It is of interest to note that the vaginal pH is mildly

alkaline during menses It is possible that this transient

neutral or alkaline vaginal pH during menses also

con-tributes to a risk for contact dermatitis from menstrual

sanitary pads, with special concern if the bleeding episode

is prolonged

Conclusion

Vaginal mucosal metabolism is uniquely

estro-gen stimulates the maturation of a metabolically active

intermediate cell layer within the vaginal epithelium This

glycogen-rich cell layer is the source for much of the

complex content of the mucosal secretions Constituents

of the mucosal secretions, as well as support for normal

microbial flora, remain almost totally

estrogen-depen-dent The characteristically low vaginal pH is directly

linked to anaerobic vaginal mucosal metabolism, as well

as to the traditionally recognized lactobacilli and other

acid-producing vaginal microflora A low estrogen level

prior to puberty and after menopause results in inactivevaginal mucosa with little production of secretions Vagi-nal pH rises with the metabolic decline in mucosal andmicrobial glycogen-dependent anaerobic glycolysis Theresulting neutral pH after menopause most likely results

in further loss of vulvovaginal skin barrier function

4 Zhou X, Brown CJ, Abdo Z, et al Differences in the composition of vaginal microbial communities found in healthy Caucasian and black women ISME J 2007;1:121–133.

5 Huggins GR, Preti G Volatile constituents of human vaginal tions Am J Obstet Gynecol 1976;126(1):129–136.

secre-6 Cauci S, Hitti J, Noonan C, Agnew K, Quadrifoglio F, Hillier SL, Eschenbach DA Vaginal hydrolytic enzymes, immunoglobulin against Gardnerella vaginalis toxin, and early risk of preterm birth among women in preterm labor with bacterial vaginosis or interme- diate flora Am J Obstet Gynecol 2002;187:877–881.

7 Preti G, Huggins GR Cyclical changes in volatile acidic metabolites

of human vaginal secretions and their relation to ovulation J Chem Ecol 1975;1:361–376.

8 Preti G, Hugins GR Organic constituents of vaginal secretions In: Hafez ESE, Evans TN (eds) The Human Vagina New York: North- Holland, 1978, pp 162–163.

9 Gross M Biochemical changes in the reproductive cycle Fertil Steril 1961;12(3):245–262.

10 Society of Obstetricians and Gynecologists of Canada The detection and management of vaginal atrophy Int J Gynecol Obstet 2004; 88:222–228.

11 Weinstein L, Howard JH The effect of estrogenic hormone on the H-ion concentration and the bacterial content of the human vagina with special reference to the Doederline bacillus Am J Obstet Gyne- col 1939;37:698–703.

Table 24.1

Menopausal effects Decreased glycogen to support lactobacillus and other microbes

Decreased glycogen to support mucosal metabolism in the intermediate cell layer

Significant loss of the metabolically active intermediate cell layer

Decline in protective mucosal secretion Decline in hydrogen ions and other secretory products in the vaginal fluid

250 24 Vaginal Secretions with Age

12 Weinstein L, Bogin M, Howard JH, Finkelstone BB A survey of the

vaginal flora at various ages with special reference to the Doederline

bacillus Am J Obstet Gynecol 1936;32:211–218.

13 Raskoff AE, Feo LG, Goldstein L The biologic characteristics of the

normal vagina Am J Obstet Gynecol 1943;47:467–494.

14 Tsai CC, Semmens JP, Semmens EC, Lam CF, Lee FS Vaginal

physi-ology in postmenopausal women: pH value, transvaginal

electropo-tential difference, and estimated blood flow South Med J 1987;

80:987–990.

15 Gorodeski GI, Hopfer U, Liu CC, Margles E Estrogen acidifies

vaginal pH by up-regulation of proton secretion via the apical

membrane of vaginal-ectocervical epithelial cells Endocrinology.

2005;146(2):816–824.

16 Bo WJ The effect of progesterone and progesterone-estrogen on the

glycogen deposition in the vagina of the squirrel monkey Am J

Obstet Gynecol 1970;107:524–530.

17 Ayre WB The glycogen-estrogen relationship in the vaginal tract.

J Clin Endocrinol Metab 1951;11:103–110.

18 Weisberg E, Aytin R, Darling G, et al Endometrial and vaginal effects

of dose-related estradiol delivered by vaginal ring or vaginal tablet Climacteric 2005;8:83–92.

19 Kunin CM, Evans C, Barhholomew D, Bates G The antimicrobial defense mechanism of the female urethra: a reassessment J Urol 2002;168:413–419.

20 Berg RW, Milligan MC, Sarbaugh FC Association of skin wetness and pH with diaper dermatitis Pediatr Dermatol 1994;11:18–20.

21 Fluhr JW, Kao J, Jain M, et al Generation of free fatty acids from phospholipids regulates stratum corneum acidification and integri-

ty J Invest Dermatol 2001;117:44–51.

22 Mauro TM SC pH: measurement, origins, and functions In: Elias

PM, Feingold KR (eds) Skin Barrier New York: Taylor & Francis,

2006, p 225.

23 Hachem JP, Crumrine D, Fluhr J, Brown BE, Feingold KR, Elias PM.

pH directly regulates epidermal permeability barrier homeostasis and stratum corneum integrity/cohesion J Invest Dermatol 2003; 121:345–353.

Vaginal Secretions with Age 24 251

58 Aging-associated Non-melanoma Skin

Cancer: A Role for the Dermis

Davina A Lewis Jeffrey B Travers Dan F Spandau

Introduction

The American Cancer Society estimates that well over one

million patients are diagnosed with skin cancer each year,

representing over half of all invasive and in situ cancers

magni-tude of these statistics suggests that the treatment of skin

cancer in the United States is a problem both for patients

and for the healthcare system Conclusive evidence has

demonstrated that the main environmental risk factor for

developing skin cancer is exposure to the ultraviolet

com-ponents in sunlight, primarily ultraviolet B wavelengths

there is a strong correlation between the development of

skin cancers are found in people over the age of 60;

therefore, age is also a risk factor for the development of

epidermis and skin cancer is obvious, the mechanism

responsible for this relationship remains obscure Recent

in vitro evidence as well as epidemiological data suggest

one possible mechanism may involve alterations in the

insulin-like growth factor-1 receptor (IGF-1R) signaling

fibroblasts support the proliferation of keratinocytes in

dermal fibroblasts age, their capacity to produce IGF-1 is

severely diminished; therefore, aged skin keratinocytes are

drop in IGF-1 expression is critically important for

non-melanoma skin carcinogenesis because adequate levels of

IGF-1 are required to prevent UVB-induced mutations in

keratinocytes In vitro and in vivo studies have shown that

IGF-1R activation protects the epidermis from initiating

relationship between aging and cancer, the critical features

of non-melanoma skin cancer (NMSC), and the newly

proposed role for the dermis in driving the development

of aging-associated NMSC

Aging and CarcinogenesisEvidence accumulated thus far definitively links increas-ing age and the onset of cancer; in fact, the greatest risk

and the incidence of cancer rises with increasing age until

primarily afflicts geriatric patients However, the isms behind the link between cancer and aging are onlybeginning to be understood Many explanations definingthe relationship between aging and carcinogenesis havebeen postulated but few have been conclusively proven Acommon theory describes the long passage of time re-quired between the creation of initiated cells containingfixed DNA mutations and the phenotypic appearance oftumors containing the descendent clones of the original

sequen-tial changes seen in the carcinogenic process require manyyears if not decades to develop, ensuring that apparent

studies have shown that the ability of individuals to tively prevent the occurrence of initiated cells through

Aging cells have an increased number of somatic tions, probably through a combination of DNA damage as

muta-a result of environmentmuta-al fmuta-actors muta-and muta-an enhmuta-anced rmuta-ate of

capability to repair DNA lesions diminishes, the frequency

of newly initiated potentially neoplastic cells increases

as well as the probability of identifiable neoplasia Morerecently, studies have identified age-dependent changes instromal tissue which provide an increasingly favorable

cells in these support tissues age, they frequently begin

to lose control of normal gene expression and cellular

charac-terized by an inflammatory phenotype that can promotethe growth of previously initiated cells or enhance the

M A Farage, K W Miller, H I Maibach (eds.), Textbook of Aging Skin, DOI 10.1007/978-3-540-89656-2_58,

# Springer-Verlag Berlin Heidelberg 2010

Non-melanoma Skin Cancer: The

Epidermis

Cancers of the skin are the most common cancers to

signifi-cant morbidity and exorbitant healthcare costs associated

with the management of skin cancer provide substantial

evidence of the need for research in this field The primary

environmental factor influencing the development of skin

cancer is exposure to ultraviolet wavelengths in sunlight

people over the age of 60, age is also a risk factor for the

development of skin cancer While the correlation

be-tween aged epidermis and NMSC is apparent, the

mecha-nism responsible for this relationship remains enigmatic

The historical explanation for the correlation between

skin cancer and aging argues that UVB damage inflicted

on skin during adolescence initiates mutations in

kerati-nocytes that are selectively enriched over many decades

until enough genetic changes have gradually accumulated

in these keratinocytes that they become carcinogenic In

fact, this mechanism has been proposed to explain the

long latency period observed in other types of cancers

where there is also a correlation between the development

suggested a modification of this theory based on the

altered function of aged stromal cells (i.e., fibroblasts)

that the selection of initiated epithelial cells is accelerated

in aged tissue due to altered gene expression in senescent

In addition, the aged state of cells may play a greater role

in the initiation of carcinogenic DNA mutations than

on the origins of cancer have led to a new paradigm to

explain non-melanoma skin carcinogenesis In order

to explain the rationale for this theory of skin

carcinogen-esis, the following paragraphs will summarize the current

understanding of the effect of ultraviolet B (UVB)

irradi-ation on skin, aging-associated NMSC risk factors, and

how cellular senescence influences NMSC carcinogenesis

Effects of UVB Irradiation on the Skin

Sunlight is composed of a variety of wavelengths of light,

which can be divided into infrared, visible, and

ultravi-olet light, arranged from the longest wavelengths to the

shortest The ultraviolet (UV) spectrum can be further

divided into three classifications, UVA (320–400 nm),

Wavelengths of light in the UVC range have the potential

to cause the most damage to living organisms; however,nearly all UVC wavelengths are absorbed in the atmo-

radiation is the most abundant ultraviolet light to trate the atmosphere, although the data are still inconclu-sive as to the exact role that UVA radiation plays in

makes up only 0.3% of the total light that reaches the

UVB component in sunlight can directly damage DNA

UVB radiation only penetrates the epidermal layer of theskin Therefore, the primary cells at risk for potentialUVB-induced damage reside in the epidermis, where ker-atinocytes are the predominant cell type UVB irradiation

of the epidermis leads to UVB-induced DNA damage in

dis-tinctive signature mutations in keratinocyte DNA due tothe direct absorption of energy This DNA damage con-sists predominantly of cytosine (C) to thymidine (T)

dimerization between adjacent pyrimidines takes place

on the same DNA strand If these mutations are allowed

to persist, this DNA damage may be propagated to ter cells perhaps giving rise to proliferative diseases in-cluding basal cell carcinoma (BCC) and squamous cellcarcinoma (SCC) The importance of cellular prolifera-tion with DNA damage in carcinogenesis is elegantly illu-strated by organisms composed largely of post-mitoticcells which do not develop cancers, such as the nematode

contrast, tissues from organisms containing replicatively

duration of UVB received determines how the epidermis

keratinocyte proliferation to allow for the repair of DNAdamage before the keratinocyte re-enters the cell cycle.However, if the exposure to UVB is prolonged a combi-nation of several outcomes can occur: (1) DNA damage

is not repaired and keratinocytes undergo apoptosis,(2) keratinocytes become senescent as a tumor evasionmechanism, or (3) damage may be mis-repaired or par-tially repaired and cells continue to proliferate, propagat-ing potentially mutagenic DNA damage The first twoobservations, UVB-induced apoptosis and UVB-inducedsenescence, are part of the normal protective response ofhuman skin to UVB exposure that maintains the integrity

of the protective barrier function of the epidermis whileensuring that UVB-damaged keratinocytes are not per-mitted to replicate with DNA mutations (the appropriate

588 58 Aging-associated Non-melanoma Skin Cancer: A Role for the Dermis

UVB response) The third observation, the failure of

UVB-induced senescence leading to replication in

kerati-nocytes containing UVB-damaged DNA, represents

flawed protection from UVB damage, and the

conse-quences of failed UVB protection may include the

stabili-zation of initiating DNA mutations that could lead to the

malignant transformation of keratinocytes (an

inappro-priate UVB response) Acquired mutations in key tumor

suppressor genes such as p53, and RB are targets of UVB

be-come resistant to the fail-safe apoptotic response, and

advantage allows for clonal expansion of mutant p53

cells over time contributing to the development of

Im-portantly, p53 mutation hot-spots are common in NMSC

mutations, UVB exposure also induces

the antigen presenting capabilities of epidermal

Langer-hans cells and stimulates the release of keratinocyte

im-mune-suppressive and pro-inflammatory lipids and

UV-in-duced immune-suppression and inflammation in relation

to skin malignancies is logical since development of

can-cers requires escape from immune system function and

UVB-induced mutations, immune-suppression and

inflamma-tion, UVB is known to cause a change in epidermal

architecture and biochemistry In skin chronically

ex-posed to the sun, there is an increase in actinic lesions

UVB-induced alterations in skin biochemistry include

deregulation of growth factors and their receptors, for

example IGF-1, erbB1, erbB2; activation of mitogenic

signaling pathways such as ras, p38 and JNK MAPKs,

and inappropriate activation of transcription factors

Aging-Related Risk Factors for

Developing NMSC

As noted previously, there is a strong correlation between

the development of skin cancer and advancing age

Child-hood exposure to UV is believed to be one of the most

critical risk factors in the development of skin cancers in

epidermal keratinocytes acquire UV-induced tumorigenic

mutations in childhood which accumulate over time in

selected populations of cells that manifest as skin cancers

to the multi-stage theory of carcinogenesis where ing mutations occurring in target genes require promo-tional events to expand and form clones of mutated cells,eventually progressing and developing into cancers.People are exposed daily to oxidative stressors whichcause DNA damage that has the potential to be fixed as

there also appears to be an increase in the production ofreactive oxygen species (ROS) that may in turn increase

this, a decline in the function of the p53 protein has beenreported in the aging process that could contribute to anincrease in the frequency of mutations and tumorigenesis

mechanisms decline and therefore, may accelerate the

in cancer cells are so numerous that almost certainly otherfactors must contribute to their development Indeed,aging is also associated with a decreased immune func-

age-related changes in human T lymphocytes contributed to

a decrease in immunity against infections and neoplasms

as well as causing an increase in autoimmune diseases

decreased immune function, decreased p53 function, and

a decreased fidelity in DNA repair mechanisms withadvancing age does indeed provide a provocative environ-ment for developing cancers

Cellular Senescence and NMSCCellular senescence is defined as an irreversible arrest incellular replication in otherwise metabolically active cells.First identified as a phenomenon controlling the longevity

replicative senescence in vitro is caused by the erosion

of telomeres and an ensuing DNA-damage response

irreversible growth arrest, increased resistance to ptotic signals, changes in cell functions such as secre-tion of growth factors, cytokines, degrading enzymes, anover-expression of proteins, oncogenes and chromatin re-organization Factors leading to senescence include finitereplicative capacity via telomere shortening, DNA dam-

Although senescent cells cannot initiate DNA replication

in response to physiological mitogens, they remain ble and continue to be metabolically active The critical

via-Aging-associated Non-melanoma Skin Cancer: A Role for the Dermis 58 589

pathways identified in cellular senescence involve p53,

suggesting that senescent cells accumulate in aged tissues

cells to aging and cancer, several markers have been

high levels of HIRA (a heterochromatin protein), and

damaged teleomeres In one study examining cultured

human fibroblasts and keratinocytes, the senescent

pheno-type was absent in terminally differentiated keratinocytes,

quiescent fibroblasts, pre-senescent cells, or immortalized

in senescent dermal fibroblasts and epidermal

fibroblasts examined in geriatric primate skin have

senes-cent markers such as damaged teleomeres and high levels

of senescent cells, it is reasonable to propose that cellular

senescence may contribute to age-related cancers by

alter-ing the surroundalter-ing tissue into a neoplastic promotalter-ing

environment The paradoxical effect of cellular senescence

on an organism’s well-being has been called antagonistic

a powerful tumor suppressor limiting cell lifespan and

removing damaged cells from a proliferative state

hand, the accumulation of senescent cells may contribute

to aging and provide a tumor promoting environment

due to their altered properties such as stromal matrix

reorganization and/or degradation, secretion of growth

Inflamma-tion is an important factor promoting carcinogenesis For

example, lesions visually described to be solar keratosis

were identified as squamous cell carcinoma histologically

accumulation of senescent cells in aging tissue may serve

to maintain tissue architecture but inadvertently due to

their altered function, change the surrounding tissue

mi-lieu to an environment where damaged and mutated cells

can more easily become malignant Evidence to

substan-tiate this hypothesis comes from investigations in which

human senescent fibroblasts were found to stimulate

pre-malignant and pre-malignant cells to proliferate in culture

and form tumors in mice due in part to

senescence-induced secretion of soluble and insoluble factors

K-rasV12 model for cancer initiation showed that

senes-cent cells only existed in pre-malignant and not malignant

tumors suggesting senescence may be an indicator in the

Non-melanoma Skin Cancer: The DermisHistorically, aging-associated NMSC is believed to becaused by the accumulation of damaged cells over dec-ades For example, one of the first signs of precancerousNMSC in aged individuals has been the appearance ofactinic lesions These lesions are readily apparent in theepidermis and are treated at the level of the keratinocyte.However, what if arising actinic damage could be pre-vented, and thereby NMSC, by detecting changes beforethey have reached the epidermis? The answer to thisquestion may be underneath the epidermis in the dermis.Considering the essential role the dermis has on epider-mal function, it is surprising that it was only a decade agothat attention was drawn to age-related changes in thedermis Therefore, although the target cell of NMSCresides in the epidermis, it is necessary to re-examinethe role the dermis may play in the development ofNMSC

Dermal and Epidermal SynergismThe proper functioning and well-being of the skin isreliant on synergistic interactions between the dermalfibroblasts and epidermal keratinocytes The integration

of all signals received by a keratinocyte will determine thespecific path that a cell takes at any given time duringdifferentiation The dermis contains a variety of cell typesincluding fibroblasts, macrophages, mast cells, dendriticcells and dermal T-lymphocytes Composed of extracellu-lar matrix, collagen and elastin fibers, the stroma andsome basement membrane components are synthesized

by dermal fibroblasts, which produce soluble factors moting survival and growth of the tissue When it isnecessary to remodel or repair the tissue, fibroblasts pro-duce a mixture of degrading enzymes, cytokines, andgrowth factors The influence of the dermis on the epi-dermis, and vice versa, is far reaching In studies wheresite-matched papillary or reticular dermal fibroblasts wereused to construct in vitro skin equivalents, the epidermalmorphology, the formation of the basement membrane,and the terminal differentiation status were influenced by

composed of papillary fibroblasts, epidermal cytes were morphologically symmetrical and all levels

keratino-of terminal differentiation were expressed Whereas skinequivalents constructed using reticular fibroblasts impededthe formation of the basement membrane and terminal

590 58 Aging-associated Non-melanoma Skin Cancer: A Role for the Dermis

number of fibroblasts used to construct the dermal matrix

of skin equivalents also appears to be essential in

The Dermis, the Immune System, and

Inflammation

What about the role of the dermis in skin immunity? The

dermis has its own armory of weapons to impede the

progress of any invader which has compromised the

epi-dermis Acting as a sentinel, the epidermis defends against

environmental and pathogenic invasion The epidermis is

equipped with Langerhans cells and T-cell

receptor-expressing dendritic epidermal T-cells (DETC) to cope

with incoming insults A substantial list of dermatologic

diseases can cause epidermal immunity to go awry, such

balance between epidermis and dermis DETC produce

and respond to insulin-like growth factor I (IGF-1) In

mice that are deficient for DETC, the epidermal balance is

tipped from proliferation to apoptosis and levels of

insu-lin-like growth factor receptor (IGF-1R) are decreased

imbalance highlighting the influence of the immune

sys-tem on growth factors in the epidermal–dermal

are the most abundant cells of the dermis and have a key

role in the structural integrity, mechanical strength and

landscape of the extracellular matrix (ECM) Fibroblasts

secrete both collagen and matrix metalloproteases that

regulate ECM turnover Adding to their resume,

fibro-blasts have also been shown to trigger and alter the

in-flammatory response as well as aid in wound healing

immune response may be driven in part by fibroblasts

known to produce (tissue specific) pro-inflammatory

Inflammation leads to further activation of fibroblasts and

This persistent vicious cycle has been well established for

fibroblasts and results in chronic inflammation Chronic

inflammation can be started and sustained by disease

states, cancer and activated fibroblasts Chronic

inflam-mation is also well known to be involved in all stages of

carcinogenesis In many cases inflammation is

therapeu-tically treated at the level of an immune cell or blockade

that fibroblasts can indeed initiate, promote and sustain

inflammation should make them attractive new target foranti-inflammatory and anti-cancer therapeutics

Dermal Aging, Senescence, and Cancer

In 1956, Harman et al suggested that free radicals wereinvolved with the deterioration of human biochemistry

reac-tive oxygen species (ROS) were shown to cause DNA

Organism aging is therefore thought to be at least in partdue to accumulation of this free radical damage over time

mechanisms preventing or scavenging ROS formed andrepairing DNA damage Currently, aging-associated skincancer has been hypothesized to be a direct result of DNAdamage accumulating over time until a threshold isreached overwhelming the tissue resulting in skin cancers

response to stress is a state of arrested growth and alteredfunction called senescence

cell that had reached the end of its proliferative capacity inculture Even though these cells had lost their proliferativecapacity they remained viable Some of the characteristic

of senescent cells are growth arrest, resistance to apoptotic

where homeostasis hinges on precise interactions betweenepithelial and mesenchymal cells, presence of senescentcells may disrupt the proper function of the tissue and

As humans age, there are many significant changes thatoccur in the body, of these the most outwardly visible arethe changes to the skin Loss of tone/elasticity, increasedpigmentation and transparency are all commonly visible

underlying biological, chemical and molecular changesgoing on under those outwardly visible changes Cellular

on by DNA damage, oncogene dysfunction, other forms

of stress, chromatin damage and telomere shortening(accelerated by oxidative damage), senescent cells arealso found to accumulate in during normal epidermal

or disrupt the normal functioning of skin is unknown.What effect they have on the surrounding tissue microen-vironment, adjacent cells, as well as the role they have indisease processes such as skin cancer is only just beginning

Aging-associated Non-melanoma Skin Cancer: A Role for the Dermis 58 591

to be unearthed Some of the changes, such as secretion

of growth factors, cytokines and degrading enzymes as

well as changes in gene expression, have been seen in

senescent cells

A New Role for the Dermis in

Aging-Associated NMSC

As discussed, the central dogma correlating the link

be-tween skin cancer and aging is that UVB-induced skin

damage during childhood and early adolescence initiates

mutations in keratinocytes Subsequently, these

keratino-cytes containing mutations acquire a growth advantage

that over many decades to become carcinogenic However,

can it be presumed that time is the sole contributor

to UVB-induced skin cancers? It is reasonable then to

consider that the physiology of aging may also lend a

hand to carcinogenic events Recent data from a variety

of labs have led to a modification on the origin of

aging-associated skin cancer based on the accumulation of

new paradigm further substantiates the importance of

the interaction between dermal fibroblasts and epidermal

keratinocytes in preventing the initiation of

carcino-genic events These interactions are dependent on

IGF-1/IGF-1R signaling which play an important role in

Role of the IGF-1R and IGF-1 in the Skin

The stroma and some basement membrane components

are synthesized by stromal fibroblasts which also produce

soluble factors that promote survival and growth of the

tissue When it is necessary to remodel or repair the tissue,

stromal fibroblasts produce a mixture of degrading

enzymes, cytokines, and growth factors The health and

proper functioning of the skin is highly dependent on the

synergistic interactions between the dermal fibroblasts and

epidermal keratinocyte One factor regulating the

interac-tion between dermal fibroblasts and epidermal

express the IGF-1R but do not synthesize IGF-1 Dermal

fibroblasts support the proliferation of epidermal

kerati-nocytes by secreting IGF-1 The mature IGF-1R consists of

four subunits, two identical extracellular alpha and two

identical transmembrane beta subunits The two alpha

and alpha-beta subunit structures are maintained by

dis-ulphide bridges IGF-1, IGF-2 and high concentrations of

insulin can activate the IGF-1R resulting in tyrosine kinase

activity Subsequently, binding or phosphorylation of

cellular substrates in close proximity via SH2 bindingdomain leads to downstream signaling The importance

of IGF-1R signaling in skin carcinogenesis is clearly dent from a variety of studies Transgenic mice overexpress-ing IGF-1 in the basal layer of skin epidermis exhibitedepidermal hyperplasia, hyperkeratosis and squamous papil-

been shown to be important in normal epidermal

can influence all stages of epidermal homeostasis Thecontrol of longevity has also demonstrated a critical rolefor the insulin/IGF-1 signaling pathway in invertebrate

reports have identified a key role for the IGF-1R in

The IGF-1R-dependent UVB Response of Human Keratinocytes

Experiments that assessed the role of various growth factors

on the response of keratinocytes to UVB irradiation fied that the activation status of the IGF-1R was a criti-cal component affecting UVB-induced apoptosis in vitro

withdrawal, treatment with neutralizing antibodies, ortreatment with IGF-1R-specific small molecule inhibitorsprior to irradiation increased the sensitivity of keratinocytes

the functional activation of the IGF-1R provided tion to human keratinocytes from UVB-induced apopto-sis However, an equally important observation was thatalthough the activation of the IGF-1R prevents cell death,the surviving keratinocytes cannot replicate and become

in response to UVB irradiation is a tumor evasion nism that maintains the important barrier function of theepidermis while ensuring keratinocytes cannot proliferate

mecha-in the presence of irreparable UVB-mecha-induced DNA damage.This appropriate response to UVB-irradiation prevents thepropagation of potentially neoplastic keratinocytes In con-trast, when the IGF-1R is functionally inactive at the time ofUVB-irradiation, a portion of the keratinocytes will under-

go apoptosis; however, keratinocytes that survive do notbecome senescent, do not repair UVB-damaged DNA, andthey continue to proliferate with the potential of convertingthe damaged DNA into initiating carcinogenic mutations

UVB-induced DNA damage, leading to carcinogenesis

592 58 Aging-associated Non-melanoma Skin Cancer: A Role for the Dermis

Aging and NMSC

The important in vitro discovery that epidermal

kerati-nocytes IGF-1R activation status was crucial in response

to UVB, led to a hypothesis that reduced activation of the

IGF-1R may be correlated to an increased susceptibility to

skin cancer in vivo In a retrospective epidemiological

study, it was found that type 2 diabetic patients using

insulin to treat their disease had a 2.5-fold decreased risk

of developing non-melanoma skin cancer over the controlgroup and type 2 diabetic patients using non-insulin

im-portant because insulin and IGF-1 have very similar lecular structures and high concentrations of insulin willactivate the IGF-1R Intriguingly, the protective effect ofinsulin use increased with age, implying that insulin was

mo- Figure 58mo-.1

Keratinocyte IGF-1R-dependent UVB response This cartoon demonstrates the consequences of UVB exposure to normal

human keratinocytes in vitro and the role of the IGF-1R At low doses of UVB irradiation, keratinocytes sustain mild DNA damage which can be completely repaired via normal cellular processes These keratinocytes continue to proliferate

unabatedly High doses of UVB cause extensive DNA damage that the keratinocyte cannot repair resulting in cell death via apoptosis, or even necrosis if the UVB dose is high enough Keratinocyte responses to both low and high doses of UVB

irradiation are independent of the IGF-1R activation status However, the keratinocyte response to a wide range of

intermediate doses of UVB is completely dependent on the activation status of the IGF-1R UVB irradiation of keratinocytes with activated IGF-1Rs incurs substantial DNA damage that cannot be completely repaired Because of the persistence of UVB-induced DNA damage, these keratinocytes become senescent, thus preventing the replication of UVB-damaged DNA.

It is important to note that when the IGF-1R is activated, no keratinocytes containing UVB-induced DNA lesions will be

replicating Unfortunately, when the IGF-1R is inactive in keratinocytes, this restriction on cellular replication with DNA

damage is not in effect Keratinocytes with functionally inactive IGF-1Rs that are exposed to UVB irradiation are more likely

to undergo apoptosis; however, surviving keratinocytes can continue to proliferate, thus establishing mutations from

unrepaired DNA in the daughter cells

Aging-associated Non-melanoma Skin Cancer: A Role for the Dermis 58 593

somehow protecting against the age-associated increase in

insulin activate the IGF-1R, these important data

sug-gested the clinical relevance for the involvement of the

IGF-1R signaling pathway in NMSC in vivo Recently, the

age-related changes in the IGF-1/IGF-1R signal

transduc-tion pathway have been examined in vivo The

produc-tion of IGF-1 diminishes as fibroblasts become senescent

supplying IGF-1 to epidermal keratinocytes, an age-related

decrease in fibroblast IGF-1 may result in keratinocytes in

aged epidermis having functionally deficient activation

of IGF-1R and thereby respond inappropriately to

UVB-irradiation Analysis of IGF-1 in samples of geriatric

indi-viduals showed a significant reduction in IGF-1 levels

kera-tinocyte activated IGF-1R levels were high in young adult

It has been reported that the difference between

UVB-induced DNA damage repair in young verses aged human

However, the most important point is that any DNA

damage existing whilst cell proliferation continues, leaves

the possibility for the propagation of mutations In young

adult skin where IGF-1 levels are high, the proliferation of

keratinocytes containing UVB-damaged DNA will be

pre-vented by a combination of DNA repair, apoptosis, and

stress-induced senescence This response to UVB

irradia-tion which prevents the creairradia-tion of tumor-initiated

kera-tinocytes is called the appropriate UVB response The goal

of the appropriate UVB response is to ensure the integrity

of the epidermis while preventing the proliferation of

keratinocytes that contain UVB-induced DNA damage

IGF-1, the normal UVB response is altered in aged skin

are proliferating despite the presence of UVB-damaged

DNA can be found in geriatric skin (i.e an inappropriate

UVB response is demonstrated by the restoration of the

appropriate UVB response in geriatric skin via treatment

Therefore, the age-related decrease in IGF-1 expression,

IGF-1R inactivation and proliferation with DNA damage

are major components in the development of NMSC seen

It is important to distinguish between the role that

IGF-1 plays in the initiation of UVB-induced skin cancer

IGF-1 plays in promoting a variety of epithelial tumors

IGF-1 leads to uncharacteristically decreased activation

of the IGF-1R in the epidermis When keratinocytes areexposed to UVB in the absence of IGF-1R activation, thenormal protective response to UVB is altered, so thatkeratinocytes with DNA damage fail to undergo stress-induced senescence and are capable of replicating chro-mosomes containing the UVB-damaged DNA Therefore,the lack of IGF-1R activation at the time of UVB irradia-tion increases the probability of a cancer-initiating event.Previous reports of IGF-1 increasing carcinogenesis were

in the context of promoting the growth of previously

In tissues where homeostasis is dependent on preciseinteractions between epithelial and mesenchymal cells, theaccumulation of senescent cells can disrupt the properfunction of the tissue The skin is one of these tissueswhere the dermal and epidermal components are interde-pendent on each other for the proper functioning of theorgan Therefore, cellular senescence affects the UVB re-sponse of keratinocytes in the epidermis through twodistinct and opposite mechanisms; one mechanism sup-presses UVB-induced transformation of keratinocytes andthe second mechanism promotes keratinocyte carcinogen-esis On the positive side, keratinocytes use stress-inducedsenescence as a tumor evasion mechanism The advantage

to cellular senescence versus UVB-induced apoptosis is thatsenescence maintains the cellularity of the epidermis, thuspreserving the barrier function In other words, widespreadUVB-induced keratinocyte apoptosis in the epidermis willseverely compromise the epidermal barrier function whileUVB-induced keratinocyte senescence will not In this man-ner, the induction of senescence in UVB-irradiated kerati-nocytes suppresses carcinogenesis On the negative side,cellular senescence in dermal fibroblasts will promoteUVB-induced carcinogenesis in aging skin IGF-1 expres-sion by dermal fibroblasts is critical for the appropriateresponse of keratinocytes to UVB irradiation The silencing

of IGF-1 expression by senescent fibroblasts contributes

to an increased initiation of transformed keratinocytes

by UVB exposure Furthermore, the altered inflammatoryphenotype of senescent fibroblasts may promote theexpansion of clones of initiated keratinocytes

Clinical Implications of Dermal Involvement in NMSC

Given the increase in NMSC incidence with its associatedmorbidity and cost, the prevention of these tumors hassignificant importance Present strategies for tumor pre-vention include avoiding excess UV exposure Consistentwith the notion that dermal aging (both intrinsic andextrinsic) results in an ‘‘abnormal’’ UVB response, several

594 58 Aging-associated Non-melanoma Skin Cancer: A Role for the Dermis

studies have demonstrated that sunscreen will prevent both

For patients with established actinic keratoses precursor

lesions, strategies include destruction by physical

modalities as well as by topical chemotherapy with rouracil or immune-mediated destruction with topical

established pre- or low-grade cancerous lesions, these

Figure 58.2

Skin IGF-1/IGF-1R-dependent UVB response This illustration compares the response of young skin and old skin to UVB

irradiation The dermis of young adults produces sufficient levels of IGF-1 to activate the IGF-1R on epidermal

keratinocytes The appropriate activation of the IGF-1R on keratinocytes leads to the induction of stress-induced

senescence following sufficient UVB exposure In young skin exposed to UVB, replicating keratinocytes will never contain UVB-damaged DNA; if UVB-irradiated keratinocyte cannot repair all of the UVB-induced DNA damage, they become

senescent UVB-induced senescence is a tumor evasion mechanism to prevent the establishment of initiated neoplastic

keratinocytes In contrast, the expression of IGF-1 is silenced in aged dermis The consequence of diminished dermal

fibroblast IGF-1 expression is a lack of IGF-1R activation in epidermal keratinocytes Instead of undergoing stress-induced senescence, the aged keratinocytes are able to proliferate in the presence of UVB-damaged DNA In contrast to young skin, keratinocytes possessing UVB-induced DNA lesions can replicate in geriatric skin This decrease in IGF-1 expression with

advancing age, the subsequent decrease in IGF-1R activity, and the evasion of the normal skin UVB response contribute to the increase in non-melanoma skin cancer seen in geriatric patients

Aging-associated Non-melanoma Skin Cancer: A Role for the Dermis 58 595

treatment strategies do not appear to effect the underlying

process by which aged skin is more susceptible to

neopla-sia If the major deciding feature of keratinocyte response

to UVB resides in the senescence status of the dermal

fibroblast, then this suggests novel treatments

Conclusion

One possible new treatment strategy would be to develop

methods to rejuvenate the fibroblasts to allow production

of factors such as IGF-1 Though marketed for cosmetic

purposes, skin damaging agents ranging from chemical

peels, laser resurfacing, heating of the skin, and other

wounding which would result in up-regulation of

fibro-blast genes (e.g., pro-collagen) should result in

upregula-tion of IGF-1 It should be noted that a recent study

demonstrated that the topical chemotherapeutic agent

5-fluorouracil results in the induction of dermal

agent to both remove pre-cancerous keratinocytes as

well as induce dermal wounding that could protect

against future UV exposure could result in an improved

effect Other therapeutic strategies that could share these

‘‘dual effects’’ of removal of mutated keratinocytes and

induction of dermal rejuvenation include photodynamic

therapy and topical imiquimod Future studies should

examine the dermal effects of these chemotherapeutic

therapies

Since there appears to be a protective effect of

treatment with IGF-1 could have a use in protecting

high-risk populations Currently used for short-stature

syn-dromes, IGF-1 has an established side-effect profile and

the role of aging in the development of skin cancer could

have significant clinical implications

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Aging-associated Non-melanoma Skin Cancer: A Role for the Dermis 58 599

62 Atopic Dermatitis in the Aged

Alexandra Katsarou Melina C Armenaka

Introduction

Direct and indirect observations indicate that the

preva-lence of atopic dermatitis (AD) has increased two- to

explana-tion for this increase is a higher susceptibility to

sensitiza-tion due to environmental factors and the ‘‘Western

lifestyle.’’ AD can be a very debilitating, persistent, and

population-based survey of eczema prevalence in the USA, a

sub-stantial proportion of the population has symptoms of

eczematous conditions, while 17.8 million met the

understand-ing the epidemiology of AD has been slow due to the lack

of suitable, uniformly used, simple, disease diagnostic

criteria that can be used in population surveys among

Atopic dermatitis affects mainly children According

to many epidemiological studies, in the 1-year period

prevalence measure, 5–20% of children in developed

preva-lence of AD, between countries and between urban and

rural areas within the same country, are noted in the

found a large increase in the prevalence of AD in

These results suggest that environmental factors and a

Western life style are the main causes in the development

of AD Atopic dermatitis also shows an important

adolescents and adults, no differences in social class over

time were noted

There is relatively little information concerning adult

AD Studies from the UK and Norway found that the

prevalence in adults over 20 years old is approximately

2% and less than 0.2% of adults over the age of 40 years

consid-erably lower in the elderly, compared to younger adults

A study from Thailand concerning adult-onset AD

con-cluded that the disease is not rare in adults and develops

mostly during the third decade of life The prevalence of

AD in Nigeria was 8.5%, and 24.5% of the patients hadonset after age 21 years In another report of 2,604patients attending a contact dermatitis clinic in Australia,9% suffered from AD which began for the first time afterage 20 and the main sites were generalized involvement,

AD in this age group, AD showed various types of atous lesions whose onset was in the fourth decade of life,and higher serum IgE and antibody-specific IgE antibo-dies levels than healthy people, but lower than in younger

careful evaluation, only 5.4% fulfilled the criteria of

nature and relevance of the nonallergic form of AD in

Concerning the natural history of AD, one study gests that 90% of affected children will be clear of eczemawithin 10 years, but other studies noted that only 60% ofthe children will be clear after the age of 16 and that 10%

In a study from Sweden, concerning the prognosis andprognostic factors in adult patients with AD, the majority

of adults (59%) with AD still had the disease after 25–38

prevalence of AD in children and the fact that AD inmost adults continues for many years point out thatmore adult and senile patients with AD are expected in

Quality of LifeAtopic dermatitis is one of the commonest chronicrelapsing inflammatory dermatoses, with increasingworldwide prevalence and major social and financialimplications for patients The health-related quality oflife (HRQL) in children with chronic skin diseases is atleast equal to that caused by many other chronic disorders

of childhood, with AD and psoriasis having the greatestimpact on HRQL In adults, severe chronic inflammatoryskin diseases may be considered as severe as anginapectoris, chronic anxiety, rheumatoid arthritis, multiple

M A Farage, K W Miller, H I Maibach (eds.), Textbook of Aging Skin, DOI 10.1007/978-3-540-89656-2_62,

# Springer-Verlag Berlin Heidelberg 2010

Patients with AD have a significantly lower quality of

life than the general population and healthy controls

Patients’ mental health, social functioning, and emotional

functioning seem to be more affected than physical

func-tioning, and quality of life is compromised because of

Quality of life is affected in adult AD patients and relates

both to disease severity and to mental components

Among a group of adult dermatology outpatients

evalu-ated using the Dermatology Life Quality Index, those with

AD were the highest scoring group compared to those

Concerning the degree of handicap in relation to the

choice of education and occupation, 38% of the

respon-dents abstained from a specific education or job due to

AD and there was an increased number of sick-leave days

there are both personal and social consequences of AD

noted in 57.5% of patients, while 36.5% of partners

reported that the appearance of eczema had an impact

on their sex life

Disease Subtypes, Clinical Features,

Diagnostic Criteria, and Outcome

Measurements

Subtypes of Atopic Dermatitis

Atopic dermatitis is an itchy, inflammatory, cutaneous

manifestation of a systemic disorder that also includes

asthma, allergic rhinitis, and food allergy AD is an atopic

disease, but all symptoms are not related to allergen

exposure Two subtypes of AD are distinguished: the

‘‘extrinsic type,’’ associated with polyvalent IgE

sensitiza-tion against inhalant and/or food allergens, and the

‘‘intrinsic type,’’ without elevated IgE levels and no

sensi-tization to inhalant or food allergens Both forms of AD

have the same clinical phenotype and associated

eosino-phila Discrimination between the two types is important,

because sensitization correlates with more severe skin

disease, and prevention and treatment are more

Intrinsic AD tends to have a late onset in childhood

men-tioned, a recent investigation suggests that the intrinsic

type of AD is a very rare entity in adults and this raises the

need to clarify the relevance of the intrinsic AD in aged

16 patients with senile AD, more than 65 years old,

12.5% had intrinsic AD, based on serum IgE levels and

Clinical Features

AD usually starts in early childhood The clinical pictureand the distribution of the lesions vary depending on theage of the patient, the duration, and complications ofeczema No single diagnostic criterion exists for AD, butthere are a multitude of major and minor features Dryskin (xerosis) occurs in most atopic patients and is persis-tent It is caused by reduced water content capacity of thestratum corneum and frequent irritation

Pruritus is an important clinical symptom of AD and

it is essential for the diagnosis of active disease It is alwayspresent in all phases of AD and in all ages and can be verysevere, often disrupting the sleep of patient The mecha-nism of pruritis is not completely understood Severalmediators such as neuropeptides, proteases, cytokines,and nerve growth factor are associated with itch in AD

In most cases of AD typical, age-related, clinical

Infantile phase (0–2 years) In most cases, AD startswithin the first 3–6 months of life and is characterized bydry, erythematous, scaling areas, symmetrically located,

on the cheeks, chin, perioral, and paranasal region,

where-as infantile eczema tends to spare the diaper area In moresevere disease, vesicular and infiltrated plaques evolve thathave a tendency for oozing and crust formation and

Figure 62.1

Case 1.

AD in a 62-year-old woman with a history of allergic rhinitis Inflammation and lichenification are apparent in the extensor surface of the left arm

640 62 Atopic Dermatitis in the Aged

secondary infections may complicate the condition

In-volvement of the hands, limb folds, upper trunk, arms,

and legs is not unusual The course of AD is relapsing and

over time, the exudative character of dermatitis is lost

Childhood phase (2–12 years) The inflammatory

lesions are characteristically located on flexural areas

and signs of lichenification appear Very often, the clinical

picture is polymorphous, due to the coexistence of

chron-ic and acute types of eczema Skin thchron-ickening, lchron-icheni-

licheni-fication, scratching due to persistent pruritus, acute

erythema, with erosive or infected skin lesions, may affectthe same area

Adolescent and adult phase The main findings aredry skin, flexural inflammation and lichenification, handand foot dermatitis, and inflammation around the eyes andneck A variety of clinical manifestations of acute phase(scaling plaques with vesicular erosive lesions) and chronicphase (lichenification), with persistent itching, coexist inmost of cases In addition, a large proportion of adults withsensitive skin and/or irritant contact dermatitis affectingthe hands had atopic eczema when they were children Infact, the hands seem to be the most common site of AD inadulthood The prevalence of hand dermatitis is 2–10 timeshigher in atopics, and occupational irritants (daily expo-sure to water, chemicals, detergents) and domestic workfavor the development of hand eczema

Senile phase Characteristics of AD in the senile phaseremain unclear and clinical features resemble the adult

Patients suffering from AD very often present withatypical clinical manifestations, that may be site-specific(infra-auricular striae, atopic winter feet, cheilitis, hyper-linearity of palms and soles, etc.) or clinical morphology-specific (follicular eruption, pityriasis alba, nummulareczema, keratosis pilaris, white dermographism, etc.)

Several factors influence the course of AD, includingclimate, textiles, and sweating

Climate In most patients, eczema is aggravated ing winter, probably due to decreased humidity Changefrom a subarctic to a subtropical climate improves skinsymptoms and quality of life in patients with AD

dur-Textiles Wool and synthetic fabrics cause irritationand itching Patients are also sensitive to irritation fromdetergents and many chemicals

Sweating is a cause of itching and exacerbation ofeczema

Unfavorable prognostic factors for AD are persistentdry or itchy skin, widespread dermatitis, associated aller-gic rhinitis, family history of AD, asthma, early age of

Diagnostic Criteria and Outcome Measurements

The diagnosis of AD is made clinically and as the clinicalmanifestations are numerous, many diagnostic criteria areused in order to confirm the diagnosis The Hanifin andRajka diagnostic criteria have been most extensively vali-dated from 1980 and they propose 4 major and 23 minor

Lichenifications on the neck and upper back with

postinflammatory diffuse hypo- and hyper-pigmentation

Atopic Dermatitis in the Aged 62 641

diagnostic criteria for AD [15] A diagnosis is established

if three of the major and three or more of the minor

criteria occur in the patient

A scoring system developed by the European Task

Force on Atopic Dermatitis (SCORing Atopic

Dermatitis-SCORAD) is one of the best outcome measurements for

atopic eczema While Hanifin’s and Rajka’s criteria are

useful for differential diagnosis, SCORAD is used to

eval-uate the severity of disease in clinical and epidemiological

studies It takes into account the extent of skin lesions, the

severity of the clinical features, and the subjective

Pathogenesis

Atopic eczema is a multifactorial chronic inflammatory

skin disease with a complex background that is

character-ized by genetic influences, skin barrier dysfunction, and

immune deviation with hyper-reactivity to environmental

stimuli and deficient antimicrobial immunity

Genetics of Atopic Dermatitis

The evolution of atopic dermatitis is influenced by genetic

and environmental factors AD is a complex genetic

disor-der and the mode of inheritance and the genes involved are

influ-ence in the course of AD comes initially from twin studies

The difference in concordance rates between monozygous

and dizygous twins gives an indication of the heritability of

inheritance of AD does not fit a simple Mendelian pattern

and more than one gene is responsible for the evolution of

the disease The MHC complex has certainly been

impli-cated and the cluster of interleukins on human

chromo-some 5 plays an important interactive role in the final

Several genetic studies suggest a linkage between AD and

the filaggrin gene, located on the epidermal

high-throughput methods for gene identification, such as

DNA micro-arrays and whole-genome genotyping, will

Skin Barrier Function in Atopic Dermatitis

The most common symptoms in patients with AD

are itching and dry skin, involving both lesional and

non-lesional skin The skin barrier is known to be aged in patients with AD There is a four- to eightfoldincrease in transepidermal water loss (TEWL) in clinicallyactive dermatitis and a two- to fivefold increase in TEWL

Many studies have focused on altered content of tum corneum lipids, as the etiology of barrier permeabili-

stra-ty dysfunction Ceramides comprise more than 50% ofthe lipids and serve as the major water-retaining mole-cules in the extracellular space of the cornified envelope.They ensure that the skin barrier is as tight as possible

and non-lesional skin of patients with AD In particular,reduction in ceramide 1 and 3 correlated with barrierdysfunction A possible explanation for this is that sphin-gomyelin metabolism is altered in AD, resulting in de-creased synthesis of ceramides, and/or that the skin ofpatients with AD is colonized by ceramidase-secretingbacteria, which may contribute to the ceramide deficiency

skin is also deficient in ceramide, as compared with that

indi-cate that decrease in stratum corneum lipids, especiallyceramides, is a major etiologic factor for atopic dry skin

A deficit of n-6 essential fatty acids (linoleic acid,g-linolenic acid, columbinic acid) can lead to an inflam-

linoleic acid tend to be elevated, but concentrations oflinoleic acid metabolites are reduced, due to reduced

administration of gamma linolenic acid seems to improveatopic eczema

Furthermore, increased skin pH in AD enhancesthe action of proteases that cause breakdown of the skin

skin pH

Recent studies have identified mutations in the tum corneum chymotryptic enzyme (SCCE) protease

conse-quence of this alteration in the SCCE gene is to producehigher levels of SCCE protease Proteases cause prematurebreakdown of corneodesmosomes, basic for the structuralintegrity of the stratum corneum, leading to a thin skinbarrier and increased penetration of irritants, microbes,

long-term application of topical corticosteroids, ally increase production of SCCE

addition-Several other genetic variations that affect skin barrier

epi-dermal barrier protein fillagrin gene, resident in the

642 62 Atopic Dermatitis in the Aged

epidermal differentiation complex, have recently been

identified as an important predisposing factor for eczema

significance, because it is often the earliest sign of the

atopic march and confirms the importance of epidermal

barrier disruption as a primary event in the evolution of

the disease Fillagrin mutations are found in more than

50% of individuals with eczema and may indicate poor

prognosis in AD, predisposing to eczema that persists into

The impaired skin barrier function may contribute to

the increased penetration of microbes and antigens and

to cutaneous hyper-reactivity with increased susceptibility

function are associated with protein allergy in AD

patients, because Langerhans cells take up antigen easily

from the damaged skin barrier Well-documented studies

prove that the degree of epidermal barrier disruption

to a recent study, the higher the TEWL in AD, the higher

is the prevalence of sensitization to environmental

air-borne allergens These data suggest the major role of

epidermal barrier function in the pathogenesis of AD

Immune Responses in Atopic Dermatitis

Complex immunologic responses are involved in

eczema-tous skin inflammation, while deficient immunity against

microorganisms leads to increased skin infections

Immune Responses Leading to Skin

Inflammation

In atopic dermatitis, complex interactions between

im-mune cells and their products, cytokines and chemokines,

lead to a combination of immediate immune responses

and delayed cellular immune responses in the inflamed

Histopathology Acute skin lesions are characterized

by epidermal intercellular edema (spongiosis) and an

epidermal and dermal perivascular cell infiltrate in

present and mast cell degranulation is evident Chronic

lichenified lesions are characterized by epidermal

hyper-plasia and dermal infiltration that is dominated by

macro-phages, IgE-bearing Langerhans cells, activated T cells,

is induced by skin repair cytokines, such as interleukin 11

The Acute Phase of Inflammation

T cell deviation and altered cytokine and chemokine levels

inflamma-tory phase is dominated by T helper cell type 2 (Th2)cytokine responses Activated memory Th2 cells that ex-press cutaneous lymphocyte antigen (CLA) are increased

in skin lesions and in the peripheral blood of AD patients,

in local lymph nodes after the interaction of skin draining dendritic cells and enables cells to home in to the

produce interleukin 4 and 13 (IL-4, IL-13) that stimulate

B cells to produce specific IgE antibodies, while regulating T helper type 1 (Th1) responses They alsoproduce Il-5, an important cytokine for eosinophil

anti-bodies bind to corresponding receptors in skin immunecells, resulting in the release of histamine and other pro-inflammatory mediators

Dendritic cells play a pivotal role in the acute zation phase Langerhans (LCs) migrate to regional lymphnodes and prime naive T cells to expand the pool of Th2

receptor (FceRI) and bearing IgE are increased in ADlesions and must be present in order to provoke eczema-

On the other hand, regulatory T cells (Tregs) thatshould play a role in suppressing T cell responses toallergens, are absent in the skin and have a reduced sup-

phe-notype,’’ activated CD4 + CD25 + Tregs promote Th2responses in AD patients

Environmental airborne allergens, food allergens, ducts of infectious pathogens, and scratching can induceTh2 immune responses and the production of specific IgE

caused by scratching, can lead to the production of IgE

autoantibodies are found in up to 80% of AD patientsduring early childhood, as compared to 25% of adult

The Chronic Phase of Inflammation

In chronic AD lesions, T helper type 1 responses are moredominant than T helper type 2 responses, resulting incellular immune responses or delayed-type hypersen-sitivity responses Interferon-g (INF-g), produced byactivated Th1 cells, predominates in chronic skin lesions.Levels of Il-5, Il-12, and granulocyte-macrophage stimu-

Kerati-nocytes stimulated by INF-g, release high levels of

Atopic Dermatitis in the Aged 62 643

chemokines, including RANTES, that lead to further

recruitment of T cells, dendritic cells, and eosinophils to

It has been shown that the local production of IL12 in

the skin, by antigen-presenting cells and eosinophils,

induces differentiation of Th1 cells and causes the

pheno-type ‘‘switch’’ from Th2 (acute phase) to Th1 (chronic

promote chronic eczema by inducing Th1 immune

Antimicrobial Immune Defense

Atopic skin is characterized by decreased ability to

elimi-nate pathogens, as a result of defective inelimi-nate and

acquired immunity As part innate immunity,

keratino-cytes and professional antigen-presenting cells in the skin

are activated by the recognition of molecular patterns

action on Toll-like receptors (TLRs) and leads to the

production of antimicrobial peptides through a vitamin

D-dependent mechanism Antimicrobial peptides have

broad antimicrobial activity against viruses, bacteria,

acquired and results from the Th2 cytokine mileu in the

skin Since vitamin D is involved in this defense pathway,

it is possible that low vitamin D levels, often found in

older populations, might increase susceptibility to

infec-tions Finally, it appears that acquired immunity requires

robust Th1 immune responses in order to eliminate

microorganisms that come in contact with the skin,

whereas Th1 responses to invading microbes are

Environmental Triggers of Atopic

Dermatitis

Important environmental factors that trigger disease

exacerbations are food allergens, airborne allergens,

microorganisms, skin irritants, contact allergens, and

psychological stress

Foods and Airborne Allergens

Atopic dermatitis is associated with hypersensitivity to

foods and/or common airborne allergens Sensitization

increases after early infancy and remains high throughout

allergen-specific IgE antibodies to various inhalant allergens and/

or food allergens occur in 87.5% of elderly patients with

Food Allergens

In early life, AD is associated with a much higher

al-lergy causes skin rashes in 40% of children with eczema,but approximately one third of children outgrow their

A large population-based study of adolescents and adultswith AD, found that food allergy was not clinically im-

patients with persistent, more severe disease are more

Sensitized individuals can react to oral food challengeswith three clinical patterns: (a) immediate hypersensitivi-

ty reactions (urticaria, angioedema, and erythema) occurwithin a few minutes, (b) soon after ingestion, pruritusleads to exacerbation of eczema, (c) late eczematous reac-

and eczematous reactions may also be seen

Cow’s milk, hen’s eggs, wheat, soy, peanuts, tree nuts,and shellfish account for 90% of food allergic reactions in

Foods cross-reacting to birch pollen (apple, carrot, celery,hazelnut) can trigger AD in adults sensitized to birch,

in German adults, documented clinically relevant allergy

to pollen-associated foods in a subgroup of birch

In adult AD patients with a positive milk tion challenge, milk-specific IgE was found in less

using topically applied food, can elicit late eczematousreactions in some of these patients A good correlationbetween positive patch tests and late reactions toingested foods has been shown in some studies, althoughother studies show a high rate of false-positive patch test

Finally, certain foods (alcohol, food additives) maycause exacerbations of eczema through nonimmunemechanisms, by acting as irritants or pseudoallergens

adult patient after 6 weeks on a low pseudoallegen

644 62 Atopic Dermatitis in the Aged

Sensitization to airborne allergens usually develops at

about 3–4 years of age and continues to be important in

atopic dermatitis are highly sensitized to aeroallergens, as

demonstrated by skin prick tests The highest amount of

serum total IgE and aeroallergen-specific IgE has been

found in AD, compared with other atopic diseases, while

no significant age-related decrease is observed in aging

Important airborne allergens are dust mite, animal

dander, grass, birch, molds, and cockroach Pruritic skin

lesions can develop after inhalation or skin exposure to

eczem-atous skin reaction that results from topical application of

airborne allergens using modified patch testing (atopy

patch tests) is similar to atopic eczema and is

character-ized by skin barrier disruption, cellular infiltration, and

(APT) in 30–50% of AD patients, whereas positive

study involving 115 adults with AD, 54% demonstrated

positive APT to least one aeroallergen, compared to 6% of

Strong evidence favors a causal role of dust mites in

parasitize the skin and release exogenous proteases that

senile AD, dust mite was found to be the most important

allergen and elevated mite-specific serum IgE levels

Finally, avoidance of dust mites has been shown to be

Microorganisms

In AD, skin barrier dysfunction, either resulting from a

genetic defect, or acquired by scratching and

environmen-tal influences, facilitates the increased penetration of

antimicro-bial immunity predisposes patients to develop bacterial

skin infections (impetigo, paronychias), localized viral

infections (herpes simplex, warts, mollusca contagiosa),

or disseminated viral infections (eczema herpeticum,

molluscatum, and vaccinatum) and fungal skin infections

Acute infections can cause AD flares, by several immune

mechanisms, including stimulating Il-12 production that

induces allergen-specific Th2 cells to home to the skin

Staphylo-coccus aureus and the opportunistic yeast Malassezia spp

evidence supports the fact that these colonizing skinpathogens can lead to eczematous skin inflammation

Skin colonization with S aureus is detected in morethan 90% of patient with AD and only in 5% of healthy

the strains isolated from skin lesions, 30–60% secrete

S aureus enterotoxins, with superantigen properties,that cause a vigorous immune response and can exacer-bate AD by promoting Th2 responses and IgE production

superanti-gens and alpha toxin also promote Th1 responses that

Finally, proteinases produced by S aureus can directly

Skin colonizing Malassezia spp yeasts (Pityrosporum)are found in up to 90% of patients with AD, compared to34% in healthy controls, and they sensitize 30–80% of

In a study of the affects of aging, anti-Malassezia IgEantibodies was found more often in adults, compared to

test reactions to Malassezia are seen in AD, especially in

Finally, observations support that decreasing skincolonization, with antibiotics or antifungal treatments,

beneficial clinical effect is only short-lived and zation occurs

recoloni-Water, Skin Irritants, and Contact AllergensWater hardness may be important in AD According to anecological study, water hardness acts on existing dermati-tis by exacerbating the disease or prolonging its duration,

Atopic skin is known to be prone to react to irritants

washing, can induce flares of AD and predispose to the

can act synergistically with allergens to increase skin

application of the irritant sodium lauryl sulfate and allergens on the skin of sensitized atopic adults, led to a

aero-Atopic Dermatitis in the Aged 62 645

more severe barrier disruption than the application of

Due to skin barrier dysfunction, contact allergens can

penetrate the skin more easily and according to a recent

study of unselected adults in Norway, AD was a risk factor

positive contact allergens increases with age in atopic

stan-dard series has been found in approximately 40% of AD

nickel, cobalt, fragrances, and rubber

Atopic dermatitis is the most common cause of

occu-pational dermatitis and doubles the risk of developing

irritant dermatitis in some occupations, particularly

those involving wet-work, although abrasive hand

exposure to irritants, or to contact allergens, can induce

the appearance of widespread eczema in atopic patients in

whom eczema was quiescent for years, or was never

present Eczema can persist even after removal from the

high-risk occupation Pre-employment counseling of

adolescents and adults with atopic eczema is crucial, so

that they can make correct decisions on their future

Psychological Factors

Patients with AD often suffer from stress-related

exacer-bations, exhaustion, depression anxiety, and helplessness

patients Atopic dermatitis patients have been described as

anxious, emotionally unstable, tense, and perfectionist;

but finally it appears that there is no specific personality

type unique to AD, and patients tend to suppress

Neuropeptides, endogenous opioids, and serotonin,

released after stress challenge, have also been associated

on blood vessel walls and act indirectly, as mediators of

inflammation, by inducing release of cytokines from mast

cells and endothelial cells, and as immuno-modulators via

corticotropine-releasing hormone

Observations that psychological stress may induce AD

flares can be explained by studies showing that stress

favors a shift in immunity toward a T helper type 2 cell

appear to have an inherited hypothalamic deficiency

that impairs normal hypothalamic–pituitary–adrenal

stress may implicate the hypophalamic–pituitary–gonadal

pathway, since female hormones generally enhance

stress, by means of increased cortisol levels that causedecreased lamellar body secretion and down-regulation

Psychologic and stress-reduction interventions haveshown to improve patient well-being and significantly

Diagnostic TestsElevation of eosinophil levels and total and allergen-specificserum IgE levels are common in AD and are associated

Sensitization to allergens can be demonstrated by surement of allergen-specific IgE antibody determination

mea-in the serum (RAST, ImmunoCAP) and by skmea-in prick tests

have in mind that skin reactivity to histamine (a positivecontrol) begins to decrease significantly after the age of 50

The induction of a local eczematous reaction afterapplication of the allergen using atopy patch tests(APTs) is another important tool for detecting relevantallergens in AD APTs should be applied to intact, un-treated skin of the back for 48 h, and read at 48 and 72 h

com-mercially available APTs can also be used for food allergytesting, preferably using freshly made extracts, since food

Oral provocation challenges (foods)

T cell-mediated (delayed)

Atopy patch tests (aeroallergens, foods, Malassezia) Standard patch tests (standard series, occupational series, medicaments)

Modified oral provocation challenges (foods)

646 62 Atopic Dermatitis in the Aged

been used in investigational units [18, 23] The

demon-stration of a positive APT reaction can reinforce the need

for allergen avoidance and this can lead to significant

clinical improvement

The diagnosis of eczematous reactions to foods inpatients with AD requires oral provocation challenges toprove the clinical relevance of history, positive skin prick

Because food-induced eczema usually needs more than 6 h

to develop and may require repeated ingestion, oralchallenge protocols need to be modified, or else positive

Further-more, a diagnostic elimination diet, lasting 4–6 weeks, isoften recommended, whereas in older patients, individu-ally tailored diet with foods that rarely cause food allergy

Finally, patch testing with a standard series of contactallergens and occupational series depending on work-place

unresponsive to topical treatment should also be tested

General Measures and Basic TreatmentThe education of the patient and/or their families, and thecommunication between doctor and patient are a veryimportant part of successful management of AD Recom-mendations and instructions must be written step by step.The avoidance of specific triggering factors (aeroallergens,foods, contact allergens) and nonspecific triggers (contactirritants, soaps, prolonged hot water showers, environ-ment with low humidity, wool and synthetic clothing,perfumes, make-up) is indicated for all patients and alltypes of AD The prevention of stress, anxiety, and depres-sion is also very important and the support of a psychol-

Topical TreatmentTopical treatment comprises the foundation of AD treat-ment and is indispensable for all patients sufferingfrom AD

Figure 62.4

Prick tests to a panel of aeroallergens applied to the

forearm Positive reactions show a local wheal and flare

(H = histamine, C = negative control)

Figure 62.5

Patch test results read at 72 h in a patient with AD An

irritant reaction to hypo-allergenic adhesive tape is

evident The right half of the photo corresponds to the area

of the back where aeroallergens (atopy patch tests) were

applied and there are no significant reactions The left half

corresponds to standard patch tests The basic European

set (upper left) showed a (++) reaction to colophony 20%,

while positive reactions to three allergens in the cosmetic

panel were also seen (lower left)

Atopic Dermatitis in the Aged 62 647

They help restore and preserve the stratum corneun

bar-rier and also decrease itching and the need for topical

treatment Emollients should be applied continuously,

even if no active inflammation is evident Ointments are

the most occlusive Urea-containing moisturizers improve

skin barrier function and reduce skin susceptibility to

irritants, whereas salicyl acid can be added to an emollient

for the treatment of chronic hyperkeratotic lesions

For-mulations containing lipids identical to those of stratum

corneum, in particular, ceramide supplementation could

better improve the dysfunctional barrier Emollients must

be applied several times daily and should be continued

long after other topical treatments have been stopped

Folliculitis is a side-effect when the occlusive action is

pronounced and in this case, the emollient must be

changed

Topical Steroids

Topical Steroids have been the corner stone of treatment

of AD for more than 50 years and are still an important

tool for the management of AD, especially for acute flares

A large number of topical corticosteroids are in use,

ranging from high to low potency of action Topical

steroids should be applied no more than twice daily, as

short-time therapy for the acute phase of AD Many

therapeutic schemes are used in order to obtain the

opti-mal therapeutic effect Intermittent use might be as

effec-tive as initial therapy with a high-potency steroid,

followed by a time-dependent dose reduction, or a change

widespread use, side effects are not very frequent for low

to medium potency topical steroids, although 72.5% of

people worry about using topical corticosteroids on their

Ultra-high and high-potency topical corticosteroids

are used for short-term treatment of lichenified areas in

adult patients To prevent tachyphylaxis, side effects and

rebound phenomena, it is proposed to use them once

daily, in combination with frequent application of

emol-lients for the first weeks and then alternate day use is

recommended

Wet-wrap dressings, using diluted steroids and/or

emollients, are very effective as a very short-term therapy

for acute erythrodermic dermatitis, therapy-resistant AD,

Topical Calcineurin Inhibitors (TCI)Pimecrolimus and tacrolimus are the two availablecalcineurin inhibitors with steroid-free, anti-inflamma-

inhibiting inflammatory cytokine transcription in vated T cells and other inflammatory cells via inhibition

acti-of calcineurin Their action is more specific than costeroids in the inflammatory process and they are notassociated with skin atrophy and thinning, striae, glau-coma, and other steroid-related side effects They can beused on the face, eyelids, neck, and any other area withsensitive and thin skin The most common side-effect is aburning sensation of the skin of short duration, related

corti-to the skin barrier dysfunction According corti-to many ical trials, no evidence of systemic toxicity or local andsystemic skin infections have been noted However, it isrecommended to minimize exposure to UVR and to usesun protective agents The early use of topical calci-neurin inhibitor can lead to better long-term diseasecontrol, with fewer flares and less need for topical corti-costeroid rescue therapy Tacrolimus ointment is moreeffective than pimecrolimus cream in adults with mod-erate to severe AD, but both agents have a similar safety

Finally, combined topical therapy, with oids and TCI, is proposed by many practitioners, becausethe two classes have different and possibly complementarymechanisms of action The recent guidelines of Interna-tional Consensus Conference on AD, recommend corti-costeroids for acute control of disease progression and asintermittent treatment in maintenance therapy with TCIs

corticoster-Topical Antimicrobials

To decrease the bacterial and fungal load on involved anduninvolved skin, topical antiseptics, such as triclosan,chlorexidine and antifungals, such as ketoconazole sham-poo, have been shown to be effective and can be topicallyused, added to bath water, or to bath emollient

According to many studies, exacerbations of AD are theresult of bacterial infections and super-infections, especially

to S aureus Topical antibiotics, alone or in combinationwith corticosteroids, are effective in mild and localizedforms Fucidin is the most popular topical antimicrobialagent in many countries, with good skin penetration, but

648 62 Atopic Dermatitis in the Aged