16th Annual Meeting European Hair Research Society

Barcelona, Spain, June 21-23, 2012

Inflammatory Phenomena

and Fibrosis in

Androgenetic Alopecia

Ralph M. Trüeb, M.D.

Center for Dermatology and Hair Diseases

Bahnhofplatz 1A

8304 Wallisellen (Zurich)

Switzerland

www.derma-haarcenter.ch

42 But if there is on the bald head or the bald

forehead a reddish-white diseased spot,

it is leprosy (tzaraath, צרעת) breaking out on

his bald head or his bald forehead.

43 In that case the priest shall examine him, ...”

Androgenetic Alopecia in the Bible (Leviticus 13:40-43)

40 "If a man's hair has fallen from his head,

he is bald but he is clean.

41 And if a man's hair has fallen from his

forehead and temples, he has baldness of

the forehead but he is clean.

Scarring Alopecia

Diverse group of disorders that cause permanent destruction of the

pilosebaceous unit and irreversible hair loss, characterized by

• visible loss of follicular ostia

• destruction of the hair follicle on histopathologic examination

• irreversibility of a potential disturbing cosmetic defect

Accounts for < 5% of dermatologic consultations for hair loss

Androgenetic Alopecia

Genetically determined, androgen induced, age-dependent progressive

hair loss with sex-dependent differences in incidence, pattern and severity,

characterized by

• typical bitemporal recession of hair and balding vertex in men and diffuse

thinning of the crown with an intact frontal hairline in women

• diversity of hair shaft diameter (anisotrichosis) on dermoscopic examination

• hair follicle miniaturization on histopathologic examination

Accounts for > 80% of dermatologic consultations for hair loss

Androgens

+

Androgen metabolism Polygenic Trait

Progressive shortening of anagen phase

+

Reduction of volume of dermal papilla

Hair follicle miniaturization

Increased shedding of hair:

Telogen effluvium

Decreased hair growth:

Terminal-to-vellus

hair transformation

anagen (2-6 years)

catagen (2 weeks)

telogen (3 months)

teloptosis

empty hair follicle

Current Concept of Pathobiology and Treatment of Androgenetic Alopecia

Role of follicular microinflammation and perifollicular fibrosis ?

Hair Follicle Microinflammation and Fibrosis

1992 Jaworsky et al refer to an inflammatory infilrate of activated T cells

and macrophages in the upper third of the hair follicle associated with an

enlargement of the follicular dermal sheath composed of collagen bundles

1993 Whiting demonstrates in morphometric studies on patients with male

pattern androgenetic alopecia (AGA) a frequency of 40% significant

perifollicular inflammation and fibrosis, and finds with 55% of patients with

follicular inflammation and fibrosis vs. 77% in those without, lesser regrowth

in response to treatment with minoxidil

2000 Mahé et al propose in a review on AGA and inflammation the term

„microinflammation“ in contrast to the inflammatory and destructive

process in the classical inflammatory scarring alopecias

2004 Deloche et al demonsrate in a study of the scalp in a large cohort of

volunteers with AGA using macrophotographs presence of peripilar signs

(PPS) around the hair ostia, and find a significant relationship between PPS

and superficial perifollicular infiltrates in early AGA

Peripilar Signs (Peripilar Cupular Atrophy)

Androgenetic alopecia without peripilar

signs

Androgenetic alopecia with peripilar

signs

Deloche et al. Arch Dermatol Res. 2004;295:422-8

Pathobiology of Perifollicular Inflammation and Fibrosis

Inflammation is a multistep process with the question arising with regard to the primary

event:

• Localization of the inflammation near the infundibulum

• Role of microbial colonization?

• Specifically, bacterial toxins, antigenic stimulus, and porphyrins?

• Role of environmental stress from irritants and pollutants?

• Role of UVR?

• Follicular keratinocytes themselves can respond to stressors by producing

radical oxygen species, nitric oxid, and releasing IL-1

• Transcription of IL-1 reponsive genes: IL-1b, TNFa, IL-8, MCP-1,-3

• Antigen presentation to T lymphocyte and induction of T-cell proliferation

• Sustained inflammation results in connective tissue remodeling (fibrosis),

where collagenases (MMP‘s) play a role,

• ultimately preventing the follicle to reform a terminal hair follicle in the course of

the hair cycle Mahé et al. Int J Dermatol 2000;39:576-584

Role of Microbial Colonization?

Folliculitis decalvans:

• neutrophilic primary cicatricial alopecia

• Staph. aureus pathognomonic

• infectious pathogen

(Personal observation)

Lichen planopilaris-like chronic stage:

• mixed inflammatory infiltrate

• sustained antigenic stimulus?

• immune pathology?

Role of Environmental Stress?

Hot comb alopecia: LoPresti et al. Arch Dermatol 1968;98:234-8

Follicular degeneration syndrome: Sperling LC, Sau P. Arch Dermatol 1992;128:68-74

Central centrifugal cicatricial alopecia (CCCA): Whiting DA, Olsen EA. Dermatol Ther 2008;2:268-78

Kyei et al identify medical and environmental risk

factors in a population study:

• Women of African origin

• Higher prevalence of diabetes mellitus II

• Hair styles causing traction

• Bacterial scalp infection Kyei et al. Arch Dermatol 2011;147:909-14

Abreu-Velez et al identify survivin, p53, MAC,

complement/C3, fibrinogen and HLA-ABC within

hair follicles in CCCA Abreu-Velez et al. N Am J Med Sci 2011;3:292-5

Role of UV Radiation?

Scalp is altered by both UV-A and UV-B

A mottled interfollicular melanoderma is related to cumulative sun exposures

There is evidence that AGA ist adversely influenced by UV exposures

Actinic field carcinogenesis of the scalp is responsible for aktinic keratoses and

SCC of the scalp

Some specific disorders such as the red scalp syndrome are restricted to UVR-

exposed scalp

Trüeb RM. Is androgenetic aopecia a photaggravated dermatosis?

Dermatology 2003;207:343-348

In 1996 Camacho et al reported a peculiar type of telogen effluvium following sunburn of

the scalp after 3 to 4 months in women with hairstyles that left areas of scalp uncovered

during prolonged sun exposure Camacho et al. Arch Dermatol 1996;132:1398-1399

It has been proposed that the columns of the cells in the hair shaft act as an efficient fibre-

optic type system, transmitting UV light downward into the hair follicle Iyengar B. Biol Signals Recept 1998;7:188-194

Piérard-Franchimont et al suggested that production of porphyrins by Propionibacterium

sp. in the pilosebaceous duct with photoactivation may lead to oxidative tissue injury and

follicular microinflammation Piérard-Franchimont et al. Exog Dermatol 2002;1:203-206

Accordingly Piérard et al found that the use of topical antimicrobials may be beneficial for

treatment of androgenetic alopecia Pierard et al. J Dermatol Treat 1996;7:153-157.

Alternatively, direct physicochemical stress from UV-R to keratinocytes with production

of radical oxygen species and nitric oxide and release of proinflammatory cytokines

may lead to injury of the putative site of follicular stem cells in the superficial portion of the

hair follicle Mahé et al. Int J Dermatol 2000;39:576-584

Role of UV Radiation?

Revised Concept of Pathobiology and Treatment of Androgenetic Alopecia

Genetic factors

Polygenic transmission: Polymorphisms of androgen

receptor?

Others?

Precipitating factors

Androgens Steroidogenic enzyme activity

Others: Microbes, irritants,

pollutants, UVR?

Follicular microinflammation

T-cells Macrophages

Langerhans cells Mast cells

Granulocytes

Follicular epithelium

Follicular stem cells

Hair matrix keratinocytes

Perifollicular fibrosis?

Hair follicle miniaturization

Androgenetic alopecia

Cytokines, growth factors, chemokines,: IL-1, TNF

TGF

IL-8, MCP-1, MCP-3 Others

Stem cell apoptosis?

Collagenases: Metalloproteinases

Dermal papilla fibroblasts

Catagen induction

Radical oxygen species, Nitric oxide

Androgen receptor

IGF-1, SCF Others?

Permanent hair lossVellus hair-

transformation

Apoptosis

1

2

3

4

5

6

8

7

Therapeutic strategies:

1. Gene therapy? (currently not available) 2. Modifiers of androgen metabolism: finasteride (available for men) 3. Antimicrobial shampoos? 4. Antiandrogens: cyproterone acetate (available for women) 5. Hair growth promoters: minoxidil (available for men and for women) 6. Antiinflammatory agents? 7. Apoptosis modulating agents? (currently not available) 8. Hair transplantation (available), implantation of dermal papilla cells or cells of follicle dermal-sheath (impending)

Therapeutic strategies:

1. Gene therapy?

2. Modifiers of androgen metabolism:

finasteride, dutasteride

3. Antimicrobial treatments?

4. Antiandrogens: CPA, spironolactone

5. Hair growth promoters: minoxidil

6. Antiinflammatory agents?

7. Apoptosis modulating agents?

8. Hair transplantation/implantation of

dermal papilla cells or cells of follicle

dermal-sheath

From: Trüeb RM. Molecular mechanisms

of androgenetic alopecia. Exp Gerontol.

2002;37:981-90.

(Postmenopausal) Frontal Fibrosing Alopecia

Original report in 1994 by Kossard as a distinct entity in postmenopausal women Kossard S. Arch Dermatol 1994;130:770-4

In 1997 revised by Kossard et al to be a frontal variant of lichen planopilaris Kossard et al. JAAD 1997;36:59-66

In 2010 Kossard suggests that this unusual alopecia may hold the key to understanding the

complex relationship of pattern alopecia, sex-related differences, and triggers for

autoimmune follicular destruction Kossard S. In: Trüeb RM, Tobin DJ. Aging Hair, Springer 2010: pp.33ff.

Fibrosing Alopecia in a Pattern Distribution

Original report in 2000 by Zinkernagel and

Trüeb

Progressive scarring alopecia in a pattern

distribution with histologic findings of:

• androgenetic alopecia with increased numbers

of miniaturized hair follicles with underlying

fibrous streamers

• a pattern of follicular interface dermatitis

targeting the upper follicle in early lesions

• perifollicular lamellar fibrosis and presence of

selectively fibrosed follicular tracts in late lesions Zinkernagel MS, Trüeb RM. Arch Dermatol

2000;136:205-11

In 2005 Olsen acknowledges existence of

clinically significant inflammatory phenomena and

fibrosis in androgenetic alopecia and proposes the

term „cicatricial pattern hair loss“ Olsen EA. J Investig Dermatol Symp Proc 2005;10:217-21

Fibrosing Alopecia in a Pattern Distribution

Androgenetic alopecia Androgenetic alopecia

with peripilar signs

(early)

Fibrosing alopecia in a

pattern distribution

(late)

Androgenetic alopecia with inflammatory phenomena and

fibrosis

Inflammatory Phenomena and Fibrosis in Androgenetic Alopecia

Follicular microinflammation and fibrosis:

Whiting D. Diagnostic and predictive value of horizontal

sections of scalp biopsy specimens in male pattern

androgenetic alopecia.

JAAD 1993;28:755-763

Kossard S. Postmenopausal frontal fibrosing alopecia.

Scarring alopecia in a pattern distribution.

Arch Dermatol. 1994;130:770-4

Zinkernagel MS, Trüeb RM. Fibrosing alopecia in a pattern

distribution: patterned lichen planopilaris or androgenetic

alopecia with a lichenoid tissue reaction pattern?

Arch Dermatol 2000;136:205-11

Follicular inflammation

and fibrosis

microscopic

localized

generalized

Degeneration of Selected Follicles by Programmed Organ Deletion?

In back skin sections form C57BL/6 mice,

perifollicular inflammatory cell clusters (PICC)

were found located around the distal non-cycling

portion of 2% of hair follicles.

PICC consisted of macrophages (MAC) and CD4+

cells.

During anagen and catagen 10% of PICC+ hair

follicles showed degenerative phenomena

reminiscent of scarring alopecia

This may indicate existence of a physiological

program of MAC-dependent controlled follicle

degeneration by which damaged or malfunctioning

follicles are removed

Scarring lopecia may represent an exaggerated

form of this physiological program

From: Eichmüller et al. J Histochem Cytochem 1998;46:361-70

Summary and Conclusions

There is substantial evidence that follicular microinflammation and fibrosis contribute

to the pathogenesis of androgenetic alopecia (AGA):

• microscopic evidence: presence of significant perifollicular inflammation and

fibrosis in 40% of AGA

• clinical evidence: peripilar signs, cicatricial pattern hair loss

• experimental evidence: perifollicular inflammatory cell clusters and macrophage-

dependent controlled follicle degeneration

Inflammation is a multistep process with the question arising with regard to the

primary event, specifically

• role of microbial colonization

• role of environmental stress

• role UVR

For the understanding of inflammatory phenomena and fibrosis in AGA we can learn

by analogy from the cicatrical alopecias

Current treatment protocols for AGA do not take account of inflammatory phenomena

and fibrosis, though morphometric studies have demonstrated that patients with

follicular inflammation and fibrosis show lesser regrowth in response to treatment

Combined Topical Minoxidil And Anti-Inflammatory Treatment

Fibrosing alopecia in a pattern distribution, F, 65 years old, after 12 months of

treatment with topical 5% minoxidil 0.2% triamcinolone acetonide lotion

(Personal observation)

Combined Topical Minoxidil And Anti-Inflammatory Treatment

Fibrosing alopecia in a pattern distribution, F, 69 years old, after 6, 12, and 15 months treatment

with oral hydroxychloroquine , and topical 5% minoxidil, 0.2% triamcinolone acetonide lotion

(Personal observation)

Thank you for your attention!

EHRS 2012 Barcelona, Spain