cicatrical alopecia

doi: 10.1111/j.1346-8138.2011.01416.x Journal of Dermatology 2012; 39: 18–26

REVIEW ARTICLE

Primary cicatricial alopecia: Recent advances inunderstanding and management

Manabu OHYAMA

Department of Dermatology, Keio University School of Medicine, Tokyo, Japan

ABSTRACT

C

To

R

18

Primary cicatricial alopecias (PCA) are a rare group of disorders, in which the hair follicle is the main target of destructive

inflammation resulting in irreversible hair loss with scarring of affected lesions. The most typical clinical manifestation of

PCA is the loss of visible follicular ostia. The histopathological hallmark of a fully developed lesion is the replacement of

the hair follicle structure by fibrous tissue. PCA could share similar clinical manifestations and eventually lead to ‘‘burn-

out’’ alopecia. Some subsets are hardly distinguishable histopathologically and the mechanisms that elicit such a

destructive reaction have not been fully elucidated. Thus, the management of PCA represents one of the most challeng-

ing clinical problems for dermatologists. The aim of this review is to provide a concise and comprehensive summary of

recent advances in PCA management, especially focusing on novel methodologies to aid diagnosis, and updates on our

understanding of the etiopathogenesis. Dermoscopy, a new pathological preparation technique and direct immunofluo-

rescence analysis enable more accurate clinicopathological diagnosis of PCA. Microarray analysis may be beneficial to

distinguish PCA subtypes. Currently suggested mechanisms underlying PCA include loss of immune protection of stem

cells, impaired stem cell self-maintenance, enhanced autoimmunity by pro-inflammatory cytokines and environmen-

tal ⁄ genetic predispositions. Interestingly, recent data indicates the association between lipid metabolism dysregulation

and PCA development, implying an important role of the sebaceous gland dysfunction in the etiopathogenesis. Based on

that hypothesis and observations, novel therapeutic approaches have been proposed, including the use of peroxisome

proliferator-activated receptor-c agonist for lichen planopilaris.

Key words: bulge, cicatricial alopecia, hair follicle, scarring, stem cell.

INTRODUCTION

Cicatricial alopecias are a group of intractable and uncommon hair

loss disorders characterized by permanent hair follicle destruc-

tion.1–5 The most typical clinical manifestation of cicatricial alopecia

is the loss of visible follicular ostia in a scarring area (Fig. 1a).4,5 The

histopathological hallmark of a fully developed lesion is the replace-

ment of the hair follicle structure by fibrous tissue (Fig. 1b).1,5,6 Cica-

tricial alopecia may result from trauma (burns, radiation, traction),

infiltrative processes (sarcoidosis, carcinomas) or infection (derma-

tophyte).2,5 In those conditions, the hair follicle is a ‘‘by-stander’’

unfortunately involved in more global damage in the scalp; thus,

permanent hair loss is a secondary event (secondary cicatricial alo-

pecia).2,5 In contrast, primary cicatricial alopecias (PCA) are a group

of disorders, in which the hair follicle is the main target of destructive

inflammation resulting in irreversible hair loss.4,5,7–9 PCA include the

conditions of varied clinical and pathological features. This, together

with inconsistent use of terminology, has hampered a comprehen-

sive definition of clinicopathological correlation,3 which has made

the study of PCA pathophysiology difficult. A breakthrough in our

orrespondence: Manabu Ohyama, M.D., Ph.D., Department of Dermatolog

kyo 160-8582, Japan. Email: [email protected]

eceived 1 September 2011; accepted 3 September 2011.

understanding of PCA was made when hair follicle stem cells were

identified in the bulge area of the hair follicle.10 Because the inflam-

mation in PCA mostly involves the bulge region, it is now widely

accepted that the loss of hair follicle stem cells is the main reason

for permanent alopecia.9,11,12 Currently, PCA attract major interest

from clinicians and also stem cell biologists as a model of organ-

specific stem cell depletion.8,9,12 In the present paper, recent

advances in understanding and management of PCA are reviewed,

especially focusing on current insights into the etiopathogenesis.

Detailed descriptions of the clinical and pathological features of indi-

vidual PCA are out of the scope of this review. For those unfamiliar

with each clinical entity, excellent review articles by the experts1,4–7,13

should help understanding.

WORKING CLASSIFICATION OF PCA

A decade ago, the North American Hair Research Society (NAHRS)

sponsored a workshop and developed a working classification of

PCA, which was mainly based on the most representative patholog-

ical finding of scalp biopsy samples.2,14 In this classification, PCA

y, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku,

� 2011 Japanese Dermatological Association

Figure 2. Working classification of primary cicatricial alopecias. AK,

acne keloidalis; AM, alopecia mucinosa; AN, acne necrotica; CCCA,central centrifugal cicatricial alopecia; CCLE, chronic cutaneous

lupus erythematosus; CP, classic pseudopelade of Brocq; DC ⁄ DF,

dissecting cellulitis ⁄ folliculitis (perifolliculitis abscedens et suffodiens);

EPD, eruptive pustular dermatosis; FD, folliculitis decalvans; FFA,frontal fibrosing alopecia; GLS, Graham–Little syndrome; KFSD,

keratosis follicularis spinulosa decalvans; LPP, lichen planopilaris.

(a)

(b)

Figure 1. Typical clinical and histopathological manifestation of pri-mary cicatricial alopecia. (a) The loss of visible follicular ostia in a

patch of scarring alopecia. (b) The replacement of the hair follicle

structure by fibrous tissue (arrowheads) (hematoxylin–eosin, original

magnification ·40).

(a)

(b)

Figure 3. Clinical presentations of lymphocytic and neutrophilic pri-

mary cicatricial alopecias. (a) Lichen planopilaris (LPP). (b) Folliculitisdecalvans (FD). Note that FD is exudative with crust formation.

Primary cicatricial alopecia

were divided into subgroups depending on the predominating

inflammatory infiltrates (Fig. 2). Chronic cutaneous lupus erythe-

matosus (CCLE), lichen planopilaris (LPP; Fig. 3a), classic

pseudoplade of Brocq (CP), central centrifugal cicatricial alopecia

(CCCA), alopecia mucinosa (AM) and keratosis follicularis spinul-

osa decalvans (KFSD) were categorized as ‘‘lymphocytic’’ PCA.

Frontal fibrosing alopecia (FFA) and Graham–Little syndrome

(GLS) were considered as LLP variants. The neutrophilic PCA

group comprised folliculitis decalvans (FD; Fig. 3b) and dissect-

ing cellulitis ⁄ folliculitis (perifolliculitis abscedens et suffodiens)

(DC ⁄ DF). Acne keloidalis (AK), acne necrotica (AN) and eruptive

pustular dermatosis (EPD) were classified as ‘‘mixed’’ cell infiltrate

PCA. In addition, non-specific cicatricial alopecia was defined as

‘‘idiopathic scarring with inconclusive clinical and histopathological

findings’’.2 The end stage of various PCA may be included in this

category as they are hardly distinguishable clinically and histo-

pathologically.2 There have been debates whether this classi-

fication is satisfactory,4 however, it provides a practical and

reasonable standard for clinical and basic studies and thus has

been widely used.

� 2011 Japanese Dermatological Association 19

(a) (b)

M. Ohyama

ADVANCES IN DIAGNOSTIC PROCEDURES

Trichoscopy (dermoscopy)The loss of follicular ostia, which is the most characteristic feature of

PCA (Fig. 1a), may not be clinically evident in some cases, but could

be clearly visualized under trichoscopy (dry dermoscopy). Indeed,

trichoscopy significantly improves the accuracy of the diagnosis of

PCA.4 Other PCA-associated signs, such as perifollicular erythema

or scale hair tufting,15 are also detectable. Trichoscopy also helps

clinicians assessing PCA disease activity. For instance, ‘‘follicular

red dots’’, erythematous polycyclic, concentric structures regularly

distributed in and around the follicular ostia, are suggestive of active

lupus erythematosus of the scalp.16 Thus, trichoscopy should be

routinely performed when PCA are considered as differential

diagnoses.

Histopathological examinationScalp biopsy is required not only to confirm PCA diagnosis but also

to determine the predominant infiltrates for classification (Fig. 4).4,5

The histological distinction between lymphocytic and neutrophilic

PCA groups is mostly possible. However, a previous study

suggested that some PCA cases within the same subgroups

were hardly distinguishable histopathologically.3

For an accurate histopathological diagnosis of PCA, biopsy

samples should be obtained from active sites and carefully sec-

tioned. Unlike in other skin diseases, the information obtained by

vertical sections is limited in hair disorders.17,18 Transverse sec-

tions enable both qualitative (e.g. inflammatory change, fibrosis)

and quantitative (e.g. hair follicle numbers, size, phase of hair

cycle) examination of scalp biopsy samples.6 Potential disadvan-

tages of transverse sectioning technique are limited visualization

of gross reaction pattern and change in the dermoepidermal

junction.7 Ideally, two 4-mm punch biopsies need to be per-

formed to prepare both transverse and vertical sections

(Fig. 4).7,19 However, multiple biopsies could burden the patients

Figure 4. Recommended sectioning for primary cicatricial alopecia

biopsy samples. HoVert technique requires less samples comparedto the combination of vertical and horizontal sections. DIF, direct

immunofluorescence; HE, hematoxylin–eosin.

20

with greater medical costs and morbidity.20 Recently, the

‘‘HoVert’’ technique, a novel processing technique which pro-

duces transverse (horizontal) and vertical sections from a single

biopsy, was described (Fig. 4).20 In this report, the authors

adopted this technique for the diagnosis of alopecia cases,

including discoid lupus erythematosus (DLE) and LPP, and con-

cluded that the HoVert technique provided more pathological

information than either vertical or horizontal sections alone.20 For

those unfamiliar with the processing of scalp samples, HoVert

preparation may be challenging. However, this new technique

should be considered, especially in situations where only a single

biopsy is allowed.

Primary cicatricial alopecia sections should be carefully investi-

gated for microorganisms (bacteria and fungus), especially when

neutrophilic infiltrates are predominant. Stains other than conven-

tional hematoxylin–eosin, such as elastica Van Gieson, Alcian blue

and periodic acid-Schiff may be beneficial.7 Previous studies

reported that a distinctive elastic staining pattern helped differential

diagnosis of advanced PCA, including pseudoplade of Brocq, LPP

and DLE.7,21,22

Direct Immunofluorescence studyAlthough the systematic histopathological investigation described

above provides a powerful diagnostic tool for PCA, inconclusive

cases may still be encountered.23 Of note, distinction between

LPP and CCLE is sometimes extremely difficult.6,13 Usefulness

of direct immunofluorescence (DIF) studies for those tackling

cases has been reported.23 The most characteristic DIF finding

of CCLE is granular deposits of immunoglobulin (Ig) and C3

(Fig. 5) at the dermoepidermal junction, while that of LPP is

globular deposits of IgM adjacent to the hair follicles or at the

dermoepidermal junction.23 DIF study is valuable in the diagnosis

(c) (d)

Figure 5. Direct immunofluorescence study is recommended for pri-

mary cicatricial alopecias. (a) Clinical presentation of chronic cutane-

ous lupus erythematosus. (b–d) Immunoglobulin (Ig) and complement

(C) deposition visualized by immunofluorescence (original magnifica-tion ·200).


Figure 6. A schematic explanation of microarray comparison of

lichen planopilaris and pseudopelade of Brocq by Yu et al.24. TotalRNA was isolated from representative lesions of two primary cicatri-

cial alopecia subtypes and used for microarray generation. Global

gene expression analysis suggested that those conditions are biolog-

ically distinct with differential gene expression pattern (hematoxylin–eosin, original magnification ·100).

Figure 7. Hair follicle stem cell populations (both established and

putative) and anatomical levels of inflammatory change in primarycicatricial alopecia. Most populations are involved in destructive

immune response.


of PCA especially in those with LPP or CCLE as differential

diagnoses.

Microarray analysisMicroarray analysis of global gene expression profile may mark a

new era in the diagnosis of PCA. There has been a debate

whether LPP and pseudoplade of Brocq are distinct diseases or

different presentation of the same pathogenic conditions, because

they can share similar clinical and pathological features.24 Micro-

array technology allows the elucidation of a broad range of molec-

ular aspects of the disease.24 In the report by Yu et al.,microarrays were generated from total RNA isolated from active

lesions of LPP and pseudoplade of Brocq and compared

(Fig. 6).24 The analysis revealed that global gene expression pro-

files in LPP and pseudoplade of Brocq based on comparative

intra-control scalp samples are different from each other with dif-

ferential expression of specific genes, suggesting that the two

conditions are biologically distinct.24 This finding demonstrated the

usefulness of microarrays for the dissection of molecular mecha-

nisms of PCA and implied the potentiality of global gene expres-

sion profiling as a diagnostic tool for clinically or pathologically

indistinguishable PCA. Furthermore, microarray comparisons


among different subtypes of PCA could enable the identification of

definitive molecular markers of each condition, which are currently

unknown.9

NEW INSIGHTS INTO THEETIOPATHOGENESIS OF PCA

Involvement of hair follicle stem cells in PCAHair follicles regenerate themselves through the hair cycle, sug-

gesting the presence of organ-specific stem cells.25,26 The land-

mark study by Cotsarelis et al. demonstrated that hair follicle

epithelial stem cells reside in the bulge region, a contagious por-

tion of the outer root sheath where the arrector pili muscle

inserts.10 Series of lineage tracking experiments demonstrated that

the bulge stem cells regenerate hair follicles in homeostasis.27–33

Indeed, permanent hair loss was observed in genetically engi-

neered mice that were designed to specifically deplete bulge stem

cells.32,33 Based on the observation that the bulge area, which is

marked by the biomarkers such as keratin-15 and -19 and

CD200,34–36 is preferentially destructed and replaced by fibrotic

tissue in PCA (Fig. 7), the loss of bulge stem cells is considered to

be a main reason for permanent hair loss in those conditions.9,11,12

Recent studies reported cell populations marked by MTS24,37

Lrig1,38 Nestin,39 Lgr540 and Lgr641 are also capable of reconsti-

tuting hair follicles, suggesting that those cells are endowed with

some stem cell characteristics (Fig. 7). The inflammation and sub-

sequent fibrosis in PCA also affect most of those populations

(Fig. 7), except Lgr5 expressing cells. Thus, irreversible damage

to hair follicle stem cells with resultant permanent hair loss still rep-

resents the most characteristic pathophysiology in PCA. However,

it should be noted that the loss of stem cells alone could not

explain other PCA manifestations, such as atrophy or follicular

plugging.9 Some additional factors should contribute to those

clinical phenotypes.

21

Figure 8. Possible mechanisms underlying primary cicatricial alope-cias. HF, hair follicle; PPAR-c, peroxisome proliferator-activated

receptor-c.

M. Ohyama

Lipid metabolism dysregulation in PCApathogenesisThe Asebia mouse, the most well-studied animal model for PCA,12

has a spontaneous mutation resulting in a defect of stearoyl-coen-

zyme A desaturase.42 The lack of this enzyme causes abnormal

fatty acid composition in the sebaceous gland leading to its atrophy

and defective secretion. This prohibits normal inner root sheath des-

quamation, enforces downward hair shaft growth penetrating into

the bulb and elicits inflammatory response that eventually destroy

the hair follicle structure (Fig. 8).43 Similar phenotypes have been

described in other rodent models with respective mutations, includ-

ing Defolliculated.9,44,45 These observations support the idea that

inflammation in scarring alopecia is a secondary event resulting

from a primary defect in the pilosebaceous unit.46 Consistent

with this, Al-Zaid et al. reported that sebaceous gland loss was a

common and early finding in PCA.47

Recently, Karnik et al. reported an intriguing data that implies a

link between lipid metabolism dysregulation and hair follicle stem cell

destruction.48 Microarray analysis identified downregulation of per-

oxisome proliferator-activated receptor-c (PPAR-c) signaling in LPP,

suggesting a central role of defective lipid metabolism and

peroxisome processing in LPP pathogenesis. Indeed, bulge stem

cell-specific depletion of PPAR-c caused scarring alopecia with focal

inflammation and lipid deposition in mice,48 suggesting that PPAR-csignaling is crucial for hair follicle stem cell maintenance (Fig. 8).

Impaired self-maintenance of hair follicle stem cellscause hair lossPermanent hair loss can also be observed in ‘‘biphasic’’ alopecias

(i.e. androgenetic alopecia, traction alopecia in which non-scarring

alopecia is observed initially but scarring alopecia develops later).13

When compared with classic PCA, direct destruction of bulge stem

cells by inflammation is less clear or hardly detectable in these con-

ditions.9 Tanimura et al. reported that loss of interaction between

Col17a1 and hair follicle stem cells impairs the self-renewal capacity

of stem cells causing permanent hair loss in mice,49 demonstrating

22

that the change in microenvironment, including decreased extracel-

lular matrix expression, alone could cause scarring alopecia. Thus,

it is possible that impaired self-maintenance or loss of self-regener-

ative potential due to environmental changes may also be responsi-

ble for PCA development (Fig. 8).

PCA and neurogenic inflammationHarries and Paus proposed the potential involvement of neurogenic

inflammation in PCA pathogenesis.9 Psycho-emotional stress upre-

gulates nerve growth factor and substance P, an inducer of neuro-

genic inflammation via mast cell degranulation in the skin and

affects hair growth and cycle in mice.50 Substance P positive nerve

fibers are dense in the bulge area51 where stress-induced perifollic-

ular inflammation and apoptosis are predominantly observed.52

In addition, given that substance P is a fibroblast growth factor,53

it could also promote scar formation in PCA (Fig. 8).9

Epithelial–mesenchymal transition (EMT) maycontribute to fibrosis in FFAPrevious studies suggested a possible contribution of EMT in renal,

liver and pulmonary fibrosis.54 Of note, lineage-tracking experi-

ments clearly demonstrated epithelial cell to myofibroblast conver-

sion, suggesting that EMT greatly contributed to the formation of

the collagen network in renal fibrosis.55 Recently, Nakamura and

Tokura demonstrated that an EMT marker, snail 1, was expressed

in the dermal fibroblasts of FFA patients. The observation suggests

a possible role of EMT conversion of hair follicle epithelial cells in the

pathogenesis of PCA (Fig. 8).

Increased apoptosis in CCLE and LPPIn PCA, apoptotic keratinocytes are frequently observed in hair folli-

cles, implying that apoptosis may play a role in PCA pathogenesis

(Fig. 8).8,9 In line with this, upregulation of p53 and Fas in keratino-

cytes, together with increase in Fas ligand-positive infiltrating cells,

were observed in CCLE.56–59 In addition, global gene expression

profiling of LPP lesions elucidated upregulation of genes involved in

apoptosis.48

Environmental and genetic factors of PCAA recent large-scale survey failed to demonstrate an obvious asso-

ciation between central hair loss and the use of a hot comb or

relaxer in an African-American woman,60 however, habitual trau-

matic hair care has been implicated in CCCA pathogenesis.61 Scalp

trauma has also been considered to play roles in the pathogenesis

of other PCA subtypes, including AK, FD and EPD.9 Of note, a pos-

sible link with EPD has been repeatedly reported.62–66 Although

evidence is still not sufficient to support a definitive conclusion,

the possibility still remains that trauma is a trigger of some forms

of PCA.

Hypersensitivity reaction to Staphylococcus aureus infection has

been implicated in the pathogenesis of neutrophilic PCA, especially

FD.9,67 In theory, superficial S. aureus infection alone is not likely to

destruct bulge stem cells and cause permanent hair loss.68 In addi-

tion, unlike lymphocytes, neutrophils are not antigen-specific and

short-lived.12 Accordingly, without continuous stimuli, chronic

inflammation observed in neutrophilic PCA could not be sustained.



Thus, S. aureus infection could induce neutrophilic PCA only when it

is coupled with some anomaly in host defense or additional events

including secondary infection.

Drugs and vaccination may induce PCA.9 Acne keloidalis may be

induced by cyclosporine.69,70 Association between imatinib and fol-

licular mucinosis was also described.71 In addition, Graham Little–

Piccardi–Lasseur syndrome following hepatitis B virus vaccination

has been reported.72

Several reports of the familial PCA cases suggested the exis-

tence of genetic factors.73–76 X-linked keratosis follicularis spinulosa

decalvans represents genetic scarring alopecias, which is caused

by a missense mutation in the MBTSP2 gene.77 Further accumula-

tion of familial PCA pedigrees could enable the identification of

gene mutations that predispose affected individuals to permanent

hair loss.

Impaired immunological stem cell protection andPCAThe loss of immunological protection of bulge stem cells is an

attractive hypothesis for preferential involvement of the bulge area

in PCA pathology.8,12 Two major possible mechanisms that defend

stem cells from unwanted immunological insults are ‘‘immune privi-

lege’’ and ‘‘non-danger’’ signal (Fig. 8).8,12,78

The term ‘‘immune privilege’’ describes intrinsic machineries to

avoid unwanted immune responses.78,79 It has been reported that

the hair follicle bulge possesses several characteristics common to

immune privilege sites, including decreased expression of major

histocompatibility complex (MHC) class I and b2-microglobulin

molecules, reduced number and impaired Langerhans cell func-

tion, increased production and secretion of immunosuppressive

molecules (indoleamine-2,3- dioxygenase, macrophage migration

inhibitory factor, a-melanocyte-stimulating hormone, transforming

growth factor and human leukocyte antigen E).12,78,80 Interestingly,

Harries et al. demonstrated the upregulation of MHC class I and II

and b2-microglobulin in the bulge in PCA affected lesions, suggest-

ing immune privilege collapse (Fig. 8).78 Although this observation

seems to provide a comprehensive explanation for inflammatory

destruction of bulge in PCA, an exact mechanism that elicits an

auto-inflammatory response has not been elucidated.8 In addition,

the possibility that those findings were secondary to inflammation

needs to be excluded.

A recent study identified CD200 as a cell surface marker of

human hair follicle bulge cells.36 CD200 is a type 1 transmembrane

glycoprotein that transmits an immunosuppressive signal through

the CD200 receptor (CD200R).81,82 Constitutive expression of

CD200 in bulge cells is thought to be a ‘‘non-danger’’ signal,83

which maintains immunocytes in a quiescent state via CD200–

CD200R interaction between the bulge cells and Langerhans cells

or other dendritic cells.12 The role of disrupted CD200–CD200R

interaction in the development of tissue-specific autoimmunity has

been proposed.84 In line with this, when CD200 null skin was grafted

onto the wild-type mice, severe cell infiltration attacking hair follicles

was provoked and permanent hair loss similar to PCA eventually

developed.85 Thus, loss of CD200 expression in the bulge is a possi-

ble mechanism that underlies PCA pathogenesis (Fig. 8). Decreased

CD200 expression was detected in the bulge area of unusual alope-


cia areata patients with a bulge involving cell infiltration,86 further

supporting this hypothesis.

Cell-mediated autoimmune response andpro-inflammatory cytokines in CCLEIt is widely accepted that PCA are categorized as autoimmune

diseases.8,12 In particular, predominance of chemokine receptor

4-expressing activated T cells87 and increase in cd-T cells88 in CCLE

lesions suggested a key role of cell-mediated autoimmunity in the

pathogenesis (Fig. 8). High levels of interferon (IFN)-a and subse-

quent enhancement of T-helper (Th)1 type immune response is a

characteristic feature of active cutaneous LE, which is reflected in

IFN-a inducible MxA protein expression.89 In scarring CCLE, lesion-

al expression of MxA was closely associated with increase in gran-

zyme B expression in skin-homing T cells expressing cutaneous

lymphocyte antigen (CLA), providing evidence that IFN and cyto-

toxic lymphocytes targeting adnexal structures are responsible for

scarring processes in CCLE.90 Other pro-inflammatory cytokines,

such as INF-c, interleukin-2 and tumor necrosis factor-a, have been

reported to be potentially involved in the pathogenesis of PCA,

including CCLE91 and LPP (Fig. 8).92

NEW HORIZON IN THE MANAGEMENT OFPCA

In PCA, the regrowth of once severely affected hair follicles can

hardly be expected. Because the stable bioengineering of human

hair follicles, especially for the clinical application, have not been

achieved,93 the goals of PCA treatment are currently limited to

relieve symptoms (not only hair loss but also itching, pain and

discomfort) and to better control ⁄ block further spread of lesions.

Given the central roles of cytotoxic autoimmune response and

host predisposition to S. aureus infection in the pathogenesis

of lymphocytic and neutrophilic PCA, respectively, the first-line

medications generally selected for the former subtype are immu-

nosuppressive agents and the latter antimicrobials or dap-

sone.4,94,95 However, currently available remedies are sometimes

of limited efficacy. Accordingly, there is a clear demand for novel

therapies.

For those patients whose PCA are well controlled and without

remaining inflammation, surgical treatments including the removal

of alopecic scar or hair transplantation may be performed and bene-

ficial.4,96 Because inflammatory cicatricial alopecias, even in a

stable ‘‘burn-out’’ stage, could be reactivated by surgery,97 the

criterion for eligibility needs to be strictly defined. For example, a

minimum 2-year disease-free period is required to undergo a surgi-

cal treatment at the University of British Columbia Hair Clinic.94

New insights into the etiopathogenesis of PCA imply the use of

novel medications for the treatment of PCA. As described above,

abnormal functioning of PPAR-c leads to aberrant lipid metabolism

in the sebaceous gland and subsequently elicits the inflammation

involving the bulge stem cells in LPP.48 Accordingly, pioglitazone

hydrochloride, an oral PPAR-c agonist, was administrated to an

intractable male case of LPP.98 Interestingly, a scalp biopsy taken

after 6 months of treatment demonstrated significant decrease in

infiltrating cells.98 He was administrated pioglitazone hydrochloride

23

M. Ohyama

for 14 months. One year after the therapy, the patient was symptom

free with no sign of hair loss,98 suggesting that PPAR-c agonists

may provide promising remedies for LPP, including its subtypes.

Also, loss of CD200 in the bulge area elicits stem cell involving

inflammation and leads to permanent hair loss in mice.85 Interest-

ingly, CD200-fc administration to experimental arthritis model mice

successfully prevented pro-inflammatory cytokine production with-

out any immunosuppressive events.99 This observation suggested

that CD200 agonists might be beneficial in PCA treatment.

CLOSING REMARKS

Despite recent advances in our understanding of the etiopathogen-

esis and the pathophysiology of PCA, the diagnosis is still challeng-

ing and the treatment may be frustrating with limited efficacy in

some cases. Once inflammation irreversibly damages the hair folli-

cle stem cell compartment, permanent loss of affected hair follicles

is inevitable. To more efficiently prevent this, treatments need to

directly target the master regulators in PCA pathogenesis. As micro-

array analysis of LPP elucidated PPAR-c dysregulation in LPP and

led to the clinical trial of PPAR-c agonist,48,98 current progress in

high-throughput screening methodology may enable the molecular

dissection of the etiopathogenesis to specify pivotal targets and,

eventually, allow the development of small molecules or biologics

for the treatment of other types of PCA. It should be emphasized

that the success of such a scenario totally depends on accurate

diagnosis, appropriate experimental design and, finally, the enthusi-

asm of clinician and patients to conquer PCA.

ACKNOWLEDGMENTS

I thank Dr Ophelia Veraitch (Department of Dermatology, Keio

University School of Medicine) for her help in the preparation

of the manuscript. I am grateful for Dr Masayuki Amagai

(Professor and Chairman, Department of Dermatology, Keio

University School of Medicine) for his critical reading of the

manuscript. Writing this manuscript was made possible in part

by the Keio Gakuji Academic Development Funds.

REFERENCES

1 Whiting DA. Cicatricial alopecia: clinico-pathological findings and treat-

ment. Clin Dermatol 2001; 19: 211–225.

2 Olsen EA, Bergfeld WF, Cotsarelis G, et al. Summary of North American

Hair Research Society (NAHRS)-sponsored Workshop on Cicatricial Alo-

pecia, Duke University Medical Center, February 10 and 11, 2001. J AmAcad Dermatol 2003; 48: 103–110.

3 Mirmirani P, Willey A, Headington JT, Stenn K, McCalmont TH, Price VH.

Primary cicatricial alopecia: histopathologic findings do not distinguish

clinical variants. J Am Acad Dermatol 2005; 52: 637–643.

4 Harries MJ, Sinclair RD, Macdonald-Hull S, Whiting DA, Griffiths CE, Paus

R. Management of primary cicatricial alopecias: options for treatment.

Br J Dermatol 2008; 159: 1–22.

5 Harries MJ, Trueb RM, Tosti A, et al. How not to get scar(r)ed: pointers

to the correct diagnosis in patients with suspected primary cicatricial

alopecia. Br J Dermatol 2009; 160: 482–501.

6 Sperling LC. Scarring alopecia and the dermatopathologist. J CutanPathol 2001; 28: 333–342.

7 Somani N, Bergfeld WF. Cicatricial alopecia: classification and histo-

pathology. Dermatol Ther 2008; 21: 221–237.

24

8 Harries MJ, Meyer KC, Paus R. Hair loss as a result of cutaneous auto-

immunity: frontiers in the immunopathogenesis of primary cicatricial

alopecia. Autoimmun Rev 2009; 8: 478–483.

9 Harries MJ, Paus R. The pathogenesis of primary cicatricial alopecias.

Am J Pathol 2010; 177: 2152–2162.

10 Cotsarelis G, Sun TT, Lavker RM. Label-retaining cells reside in the bulge

area of pilosebaceous unit: implications for follicular stem cells, hair cycle,

and skin carcinogenesis. Cell 1990; 61: 1329–1337.

11 Cotsarelis G, Millar SE. Towards a molecular understanding of hair loss

and its treatment. Trends Mol Med 2001; 7: 293–301.

12 McElwee KJ. Etiology of cicatricial alopecias: a basic science point of

view. Dermatol Ther 2008; 21: 212–220.

13 Sperling LC, Cowper SE. The histopathology of primary cicatricial

alopecia. Semin Cutan Med Surg 2006; 25: 41–50.

14 Olsen E, Stenn K, Bergfeld W, et al. Update on cicatricial alopecia.

J Investig Dermatol Symp Proc 2003; 8: 18–19.

15 Inui S. Trichoscopy for common hair loss diseases: algorithmic method

for diagnosis. J Dermatol 2011; 38: 71–75.

16 Tosti A, Torres F, Misciali C, et al. Follicular red dots: a novel dermoscopic

pattern observed in scalp discoid lupus erythematosus. Arch Dermatol2009; 145: 1406–1409.

17 Headington JT. Transverse microscopic anatomy of the human scalp. A

basis for a morphometric approach to disorders of the hair follicle. ArchDermatol 1984; 120: 449–456.

18 Frishberg DP, Sperling LC, Guthrie VM. Transverse scalp sections: a pro-

posed method for laboratory processing. J Am Acad Dermatol 1996; 35:

220–222.

19 Elston DM. Vertical vs. transverse sections: both are valuable in the evalu-

ation of alopecia. Am J Dermatopathol 2005; 27: 353–356.

20 Nguyen JV, Hudacek K, Whitten JA, Rubin AI, Seykora JT. The HoVert

technique: a novel method for the sectioning of alopecia biopsies. J CutanPathol 2011; 38: 401–406.

21 Pinkus H. Differential patterns of elastic fibers in scarring and non-scarring

alopecias. J Cutan Pathol 1978; 5: 93–104.

22 Elston DM, McCollough ML, Warschaw KE, Bergfeld WF. Elastic tissue in

scars and alopecia. J Cutan Pathol 2000; 27: 147–152.

23 Trachsler S, Trueb RM. Value of direct immunofluorescence for differential

diagnosis of cicatricial alopecia. Dermatology 2005; 211: 98–102.

24 Yu M, Bell RH, Ross EK, et al. Lichen planopilaris and pseudopelade of

Brocq involve distinct disease associated gene expression patterns by

microarray. J Dermatol Sci 2010; 57: 27–36.

25 Cotsarelis G. Epithelial stem cells: a folliculocentric view. J Invest Derma-tol 2006; 126: 1459–1468.

26 Ohyama M. Hair follicle bulge: a fascinating reservoir of epithelial stem

cells. J Dermatol Sci 2007; 46: 81–89.

27 Taylor G, Lehrer MS, Jensen PJ, Sun TT, Lavker RM. Involvement of follic-

ular stem cells in forming not only the follicle but also the epidermis. Cell2000; 102: 451–461.

28 Oshima H, Rochat A, Kedzia C, Kobayashi K, Barrandon Y. Morphogene-

sis and renewal of hair follicles from adult multipotent stem cells. Cell2001; 104: 233–245.

29 Morris RJ, Liu Y, Marles L, et al. Capturing and profiling adult hair follicle

stem cells. Nat Biotechnol 2004; 22: 411–417.

30 Blanpain C, Lowry WE, Geoghegan A, Polak L, Fuchs E. Self-renewal,

multipotency, and the existence of two cell populations within an epithelial

stem cell niche. Cell 2004; 118: 635–648.

31 Claudinot S, Nicolas M, Oshima H, Rochat A, Barrandon Y. Long-term

renewal of hair follicles from clonogenic multipotent stem cells. Proc NatlAcad Sci USA 2005; 102: 14677–14682.

32 Ito M, Liu Y, Yang Z, et al. Stem cells in the hair follicle bulge contribute to

wound repair but not to homeostasis of the epidermis. Nat Med 2005; 11:

1351–1354.

33 Nowak JA, Polak L, Pasolli HA, Fuchs E. Hair follicle stem cells are speci-

fied and function in early skin morphogenesis. Cell Stem Cell 2008; 3:

33–43.

34 Lyle S, Christofidou-Solomidou M, Liu Y, Elder DE, Albelda S, Cotsarelis

G. The C8 ⁄ 144B monoclonal antibody recognizes cytokeratin 15 and

defines the location of human hair follicle stem cells. J Cell Sci 1998; 111

(Pt 21): 3179–3188.



35 Kloepper JE, Tiede S, Brinckmann J, et al. Immunophenotyping of the

human bulge region: the quest to define useful in situ markers for human

epithelial hair follicle stem cells and their niche. Exp Dermatol 2008; 17:

592–609.

36 Ohyama M, Terunuma A, Tock CL, et al. Characterization and isolation of

stem cell-enriched human hair follicle bulge cells. J Clin Invest 2006; 116:

249–260.

37 Nijhof JG, Braun KM, Giangreco A, et al. The cell-surface marker MTS24

identifies a novel population of follicular keratinocytes with characteristics

of progenitor cells. Development 2006; 133: 3027–3037.

38 Jensen KB, Collins CA, Nascimento E, et al. Lrig1 expression defines a

distinct multipotent stem cell population in mammalian epidermis. CellStem Cell 2009; 4: 427–439.

39 Amoh Y, Li L, Katsuoka K, Penman S, Hoffman RM. Multipotent nestin-

positive, keratin-negative hair-follicle bulge stem cells can form neurons.

Proc Natl Acad Sci USA 2005; 102: 5530–5534.

40 Jaks V, Barker N, Kasper M, et al. Lgr5 marks cycling, yet long-lived, hair

follicle stem cells. Nat Genet 2008; 40: 1291–1299.

41 Snippert HJ, Haegebarth A, Kasper M, et al. Lgr6 marks stem cells in the

hair follicle that generate all cell lineages of the skin. Science 2010; 327:

1385–1389.

42 Zheng Y, Eilertsen KJ, Ge L, et al. Scd1 is expressed in sebaceous

glands and is disrupted in the asebia mouse. Nat Genet 1999; 23:

268–270.

43 Sundberg JP, Boggess D, Sundberg BA, et al. Asebia-2J (Scd1(ab2J)): a

new allele and a model for scarring alopecia. Am J Pathol 2000; 156:

2067–2075.

44 Porter RM, Jahoda CA, Lunny DP, et al. Defolliculated (dfl): a dominant

mouse mutation leading to poor sebaceous gland differentiation and total

elimination of pelage follicles. J Invest Dermatol 2002; 119: 32–37.

45 Ruge F, Glavini A, Gallimore AM, et al. Delineating immune-mediated

mechanisms underlying hair follicle destruction in the mouse mutant defol-

liculated. J Invest Dermatol 2011; 131: 572–579.

46 Stenn KS. Insights from the asebia mouse: a molecular sebaceous

gland defect leading to cicatricial alopecia. J Cutan Pathol 2001; 28:

445–447.

47 Al-Zaid T, Vanderweil S, Zembowicz A, Lyle S. Sebaceous gland loss and

inflammation in scarring alopecia: a potential role in pathogenesis. J AmAcad Dermatol 2011; 65: 597–603.

48 Karnik P, Tekeste Z, McCormick TS, et al. Hair follicle stem cell-specific

PPARgamma deletion causes scarring alopecia. J Invest Dermatol 2009;

129: 1243–1257.

49 Tanimura S, Tadokoro Y, Inomata K, et al. Hair follicle stem cells provide a

functional niche for melanocyte stem cells. Cell Stem Cell 2011; 8: 177–

187.

50 Peters EM, Arck PC, Paus R. Hair growth inhibition by psychoemotional

stress: a mouse model for neural mechanisms in hair growth control.

Exp Dermatol 2006; 15: 1–13.

51 Peters EM, Botchkarev VA, Botchkareva NV, Tobin DJ, Paus R. Hair-

cycle-associated remodeling of the peptidergic innervation of murine skin,

and hair growth modulation by neuropeptides. J Invest Dermatol 2001;

116: 236–245.

52 Arck PC, Handjiski B, Hagen E, Joachim R, Klapp BF, Paus R. Indications

for a ‘brain-hair follicle axis (BHA)’: inhibition of keratinocyte proliferation

and up-regulation of keratinocyte apoptosis in telogen hair follicles by

stress and substance P. FASEB J 2001; 15: 2536–2538.

53 Nilsson J, von Euler AM, Dalsgaard CJ. Stimulation of connective tissue

cell growth by substance P and substance K. Nature 1985; 315: 61–

63.

54 Nakamura M, Tokura Y. Expression of Snail1 in the fibrotic dermis of post-

menopausal frontal fibrosing alopecia: possible involvement of an epithe-

lial-mesenchymal transition and a review of the Japanese patients. Br JDermatol 2010; 162: 1152–1154.

55 Iwano M, Plieth D, Danoff TM, Xue C, Okada H, Neilson EG. Evidence that

fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest2002; 110: 341–350.

56 Nakajima M, Nakajima A, Kayagaki N, Honda M, Yagita H, Okumura K.

Expression of Fas ligand and its receptor in cutaneous lupus: implication

in tissue injury. Clin Immunol Immunopathol 1997; 83: 223–229.


57 Chung JH, Kwon OS, Eun HC, et al. Apoptosis in the pathogenesis of cuta-

neous lupus erythematosus. Am J Dermatopathol 1998; 20: 233–241.

58 Pablos JL, Santiago B, Galindo M, Carreira PE, Ballestin C, Gomez-Reino

JJ. Keratinocyte apoptosis and p53 expression in cutaneous lupus and

dermatomyositis. J Pathol 1999; 188: 63–68.

59 Baima B, Sticherling M. Apoptosis in different cutaneous manifestations

of lupus erythematosus. Br J Dermatol 2001; 144: 958–966.

60 Olsen EA, Callender V, McMichael A, et al. Central hair loss in African

American women: incidence and potential risk factors. J Am AcadDermatol 2011; 64: 245–252.

61 LoPresti P, Papa CM, Kligman AM. Hot comb alopecia. Arch Dermatol1968; 98: 234–238.

62 Grattan CE, Peachey RD, Boon A. Evidence for a role of local trauma in

the pathogenesis of erosive pustular dermatosis of the scalp. Clin ExpDermatol 1988; 13: 7–10.

63 Wollenberg A, Heckmann M, Braun-Falco O. [Erosive pustular dermatosis

of the scalp after zoster ophthalmicus and trauma]. Hautarzt 1992; 43:

576–579.

64 Goulden V, Layton AM, Cunliffe WJ. Erosive pustular dermatosis of the

scalp secondary synthetic fibre implantation. J R Soc Med 1994; 87:

741.

65 Layton AM, Cunliffe WJ. Erosive pustular dermatosis of the scalp following

surgery. Br J Dermatol 1995; 132: 472–473.

66 Ena P, Lissia M, Doneddu GM, Campus GV. Erosive pustular dermatosis

of the scalp in skin grafts: report of three cases. Dermatology 1997; 194:

80–84.

67 Sullivan JR, Kossard S. Acquired scalp alopecia. Part II: a review. Austra-las J Dermatol 1999; 40: 61–70; quiz 71-62.

68 Miura M, Dekio I, Yamasaki Y, Ohyama M. Sparing of the bulge area could

preserve intact lower portion of hair follicles in a case of tufted folliculitis.

J Eur Acad Dermatol Venereol 2008; 23: 87–89.

69 Azurdia RM, Graham RM, Weismann K, Guerin DM, Parslew R. Acne

keloidalis in caucasian patients on cyclosporin following organ transplan-

tation. Br J Dermatol 2000; 143: 465–467.

70 Carnero L, Silvestre JF, Guijarro J, Albares MP, Botella R. Nuchal acne

keloidalis associated with cyclosporin. Br J Dermatol 2001; 144:

429–430.

71 Yanagi T, Sawamura D, Shimizu H. Follicular mucinosis associated with

imatinib (STI571). Br J Dermatol 2004; 151: 1276–1278.

72 Bardazzi F, Landi C, Orlandi C, Neri I, Varotti C. Graham Little-Piccardi-

Lasseur syndrome following HBV vaccination. Acta Derm Venereol1999; 79: 93.

73 Collier PM, James MP. Pseudopelade of Brocq occurring in two brothers

in childhood. Clin Exp Dermatol 1994; 19: 61–64.

74 Sahl WJ. Pseudopelade: an inherited alopecia. Int J Dermatol 1996; 35:

715–719.

75 Douwes KE, Landthaler M, Szeimies RM. Simultaneous occurrence of fol-

liculitis decalvans capillitii in identical twins. Br J Dermatol 2000; 143:

195–197.

76 Viglizzo G, Verrini A, Rongioletti F. Familial Lassueur-Graham-Little-

Piccardi syndrome. Dermatology 2004; 208: 142–144.

77 Aten E, Brasz LC, Bornholdt D, et al. Keratosis Follicularis Spinulosa

Decalvans is caused by mutations in MBTPS2. Hum Mutat 2010; 31:

1125–1133.

78 Harries MJ, Meyer KC, Chaudhry IH, Griffiths CE, Paus R. Does collapse

of immune privilege in the hair-follicle bulge play a role in the pathogene-

sis of primary cicatricial alopecia? Clin Exp Dermatol 2010; 35: 637–

644.

79 Paus R, Nickoloff BJ, Ito T. A ‘hairy’ privilege. Trends Immunol 2005; 26:

32–40.

80 Meyer KC, Klatte JE, Dinh HV, et al. Evidence that the bulge region is a site

of relative immune privilege in human hair follicles. Br J Dermatol 2008;

159: 1077–1085.

81 Wright GJ, Puklavec MJ, Willis AC, et al. Lymphoid ⁄ neuronal cell surface

OX2 glycoprotein recognizes a novel receptor on macrophages impli-

cated in the control of their function. Immunity 2000; 13: 233–242.

82 Wright GJ, Cherwinski H, Foster-Cuevas M, et al. Characterization of the

CD200 receptor family in mice and humans and their interactions with

CD200. J Immunol 2003; 171: 3034–3046.

25

M. Ohyama

83 Rosenblum MD, Yancey KB, Olasz EB, Truitt RL. CD200, a ‘‘no danger’’

signal for hair follicles. J Dermatol Sci 2006; 41: 165–174.

84 Barclay AN, Wright GJ, Brooke G, Brown MH. CD200 and membrane pro-

tein interactions in the control of myeloid cells. Trends Immunol 2002; 23:

285–290.

85 Rosenblum MD, Olasz EB, Yancey KB, et al. Expression of CD200 on

epithelial cells of the murine hair follicle: a role in tissue-specific immune

tolerance? J Invest Dermatol 2004; 123: 880–887.

86 Yoshida R, Tanaka K, Amagai M, Ohyama M. Involvement of the bulge

region with decreased expression of hair follicle stem cell markers in senile

female cases of alopecia areata. J Eur Acad Dermatol Venereol(in press).

87 Wenzel J, Henze S, Worenkamper E, et al. Role of the chemokine receptor

CCR4 and its ligand thymus- and activation-regulated chemokine ⁄ CCL17

for lymphocyte recruitment in cutaneous lupus erythematosus. J InvestDermatol 2005; 124: 1241–1248.

88 Volc-Platzer B, Anegg B, Milota S, Pickl W, Fischer G. Accumulation of

gamma delta T cells in chronic cutaneous lupus erythematosus. J InvestDermatol 1993; 100: 84S–91S.

89 Freutel S, Gaffal E, Zahn S, Bieber T, Tuting T, Wenzel J. Enhanced

CCR5+ ⁄ CCR3+ T helper cell ratio in patients with active cutaneous lupus

erythematosus. Lupus 2011; 15: 15.

90 Wenzel J, Uerlich M, Worrenkamper E, Freutel S, Bieber T, Tuting T. Scar-

ring skin lesions of discoid lupus erythematosus are characterized by high

numbers of skin-homing cytotoxic lymphocytes associated with strong

expression of the type I interferon-induced protein MxA. Br J Dermatol2005; 153: 1011–1015.

26

91 Toro JR, Finlay D, Dou X, Zheng SC, LeBoit PE, Connolly MK. Detection

of type 1 cytokines in discoid lupus erythematosus. Arch Dermatol 2000;

136: 1497–1501.

92 Moretti S, Amato L, Massi D, Bianchi B, Gallerani I, Fabbri P. Evaluation of

inflammatory infiltrate and fibrogenic cytokines in pseudopelade of Brocq

suggests the involvement of T-helper 2 and 3 cytokines. Br J Dermatol2004; 151: 84–90.

93 Kobayashi T, Iwasaki T, Amagai M, Ohyama M. Canine follicle stem

cell candidates reside in the bulge and share characteristic fea-

tures with human bulge cells. J Invest Dermatol 2010; 130: 1988–

1995.

94 Ross EK, Tan E, Shapiro J. Update on primary cicatricial alopecias. J AmAcad Dermatol 2005; 53: 1–37.; quiz 38-40

95 Stenn KS, Cotsarelis G, Price VH. Report from the cicatricial alopecia

colloquium. J Invest Dermatol 2006; 126: 539–541.

96 Unger WP. Hair transplantation: current concepts and techniques.

J Investig Dermatol Symp Proc 2005; 10: 225–229.

97 Otberg N, Wu WY, Kang H, et al. Folliculitis decalvans developing

20 years after hair restoration surgery in punch grafts: case report.

Dermatol Surg 2009; 35: 1852–1856.

98 Mirmirani P, Karnik P. Lichen planopilaris treated with a peroxisome prolif-

erator-activated receptor gamma agonist. Arch Dermatol 2009; 145:

1363–1366.

99 Simelyte E, Criado G, Essex D, Uger RA, Feldmann M, Williams RO.

CD200-Fc, a novel antiarthritic biologic agent that targets proinflammatory

cytokine expression in the joints of mice with collagen-induced arthritis.

Arthritis Rheum 2008; 58: 1038–1043.


cicatrical alopecia

Documents