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Transcript of Inflammatory Phenomena and Fibrosis in … Annual Meeting European Hair Research Society Barcelona,...
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