An Overview of Alopecias - CSHL Pperspectivesinmedicine.cshlp.org/content/4/3/a013615.full.pdfAn...

An Overview of Alopecias

Ji Qi and Luis A. Garza

Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287

Correspondence: [email protected]

Hair loss is a topic of enormous public interest and understanding the pathophysiology andtreatment of various alopecias will likely make a large impact on patients’ lives. The inves-tigation of alopecias also provides important insight in the basic sciences; for instance, theabundance of stem cell populations and regenerative cycles that characterize a hair folliclerender it an excellent model for the study of stem cell biology. This review seeks to provide aconcise summary of the major alopecias with regard to presentation and management, andcorrelate these to recent advances in relevant research on pathogenesis.

ALOPECIAS: AN INTRODUCTION

Shakespeare wrote, “There’s many a manhas more hair than wit” in the Comedy of

Errors. However, in today’s contemporary soci-ety, some patients are so troubled by hair lossthey might trade wit for more hair if given theopportunity. The study of alopecia is desper-ately encouraged by society given the impor-tance of hair to most people’s identity. There-fore, a better understanding of the pathogenesisand potential treatments of alopecia will be awelcome advancement.

The study of alopecias will also broaden ourunderstanding of the basic biology of the hairfollicle, likely the most complicated structurewithin the skin. Replete with multiple stemcell populations and an intrinsic cycle of re-generation, the hair follicle has become anattractive model within the last 20 yr to studyquestions about stem cell biology. As in all bio-logical systems, the best clues to critical play-ers are instances in which their perturbationyields functional defects. Thus, human alope-

cias represent a rich arena for the study of novelcontrol points for hair follicle function. Thisarticle will cover the clinical presentations ofmajor alopecias and delve into recent researchregarding pathogenesis.

Hair itself has few physical functions. Theseinclude defense against the effects of UV radia-tion, suppression of heat loss, and tactile sensa-tion. The various hair types consist of terminal,intermediate, and vellus hairs. Terminal hairsfit the classic perception of hair and are the hairsof the scalp, axillae, pubic region, beard, eye-brows, and eyelashes. These are long, pigment-ed, and thick. Vellus hairs, on the other hand,are short and generally lack pigmentation. Thesecover the body. Intermediate hairs have char-acteristics that fall in the middle of the spec-trum between terminal and vellus hairs. Lossof hair can be irreversible, causing skin to atro-phy and follicular openings to vanish. Suchcases are categorized as cicatricial (or scarring,permanent) alopecia. Reversible hair loss isnoncicatricial (Wolff et al. 2009).

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Humans are usually born with approximate-ly 5 million follicles, and no new follicles arethought to be added after birth. The hair folliclecycle, which begins in utero, is composed ofthree stages: anagen, telogen, and catagen. Ana-gen phase is the longest, lasting an average of 3 yrand ranging from 1 to 6 yr depending on bodylocation. It is also the most prevalent phase, with90%–95% of all hairs existing in anagen phase atany one point in time. Anagen represents thegrowth period, comprising extensive mitotic ac-tivity, such that longer anagen phase means lon-ger hair (e.g., scalp as opposed to eyebrows, eye-lashes, or pubic hair). The hair then involutesduring catagen phase through apoptosis of thefollicular keratinocytes, leaving a club hair. Tel-ogen is the resting period with inactivity of theorgan, persisting 2 to 3 mo on the scalp or longerelsewhere. The club hair is shed and a new ana-gen hair grows in its place to resume the cycle(Wolff et al. 2009; Habif 2010).

Given its properties of regeneration, the hairfollicle is a fascinating organ. Learning about as-sociated pathophysiologies can yield a great dealof insight about human physiology and serve asa model of regeneration for a human organ.

NONCICATRICIAL ALOPECIAS

Androgenetic Alopecia

Clinical Presentation and Management

Androgenetic alopecia (AGA), also known aspatterned hair loss, is the most common typeof alopecia in both men and women. AlthoughAGA is a physiological condition, the psycholog-ical impact of hair loss can be profound. Half ofall men are affected by age 50, whereas 40% ofwomen are affected by age 70 (Norwood 1975,2001). However, symptoms may present as earlyas around the time of puberty. The Hamiltonclassification system describes the predominantcourse in men: a receding frontal hairline withbitemporal hair loss that merges with vertexthinning. In women, the anterior hairline ispreserved and thinning occurs primarily at thecrown, as depicted by the Ludwig pattern. Inboth cases, the condition progresses gradually.For many men, AGA advances to produce com-

plete baldness with retention of only the occip-ital and temporal hair regions. In contrast, totalbaldness at any area is rare for women. Hair lossoccurs because of the conversion of terminalhairs into vellus hairs that eventually atrophy.The process is attributed to the effect of dihydro-testosterone (DHT) on hair follicles of the scalp,causing them to gradually miniaturize. Diag-nosis is made based on clinical presentation,clinical history, and family history of AGA. Thecondition is characterized by a polygenic in-heritance pattern (Table 1) (Paus and Cotsarelis1999; Habif 2010; Otberg and Shapiro 2012).

Currently, two medications have receivedFood and Drug Administration approval in thetreatment of AGA. Minoxidil, commerciallyknown as Rogaine, is a topical vasodilator thatprolongs anagen phase and increases the sizeof smaller hair follicles. Its exact mechanismof action has yet to be worked out, but recenthypotheses involve modulation of prostaglan-din levels (Messenger and Rundegren 2004).Finasteride is an oral medication that inhibits5a-reductase type II, thereby preventing theconversion of testosterone to DHT, without adirect effect on androgen receptors. Minoxidilcan be used by both men and women, but ben-efits of finasteride have not been demonstratedin women with AGA. Both medications mustbe taken indefinitely for benefits to persist. Sur-gical treatments such as hair transplants areavailable as well; weaves and wigs also serve asoptions (Habif 2010; Otberg and Shapiro 2012).

Recent Research on Pathogenesis

Recent research has increased knowledge re-garding AGA pathogenesis and raised possibil-ities for the development of new treatment.DHT is traditionally implicated in pattern hairloss, with dermal papilla cells (DP cells) hypoth-esized as the hormone’s target that sends signalsto follicular epithelial cells. Researchers haveshown Wnt inhibitory dickkopf 1 (DKK-1), agene under DHT control, to be significantly up-regulated in DP cells located in balding scalpareas (Kwack et al. 2008). The possible up-reg-ulation of DKK-1 in AGA fits current models,given the importance of Wnt in promoting hair

J. Qi and L.A. Garza

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Table 1. Main features of various alopecias

Noncicatricial alopecias

Androgenetic alopecia

Most common type of hair loss in both men and womenOnset may be as early as puberty: 50% of men affected by age 50, 40% of women by age 70Male pattern: Thinning of the frontal hairline, bitemporal recession, hair loss at the crownFemale pattern: Hair loss at the crown with preservation of the frontal hairlineCaused by the effect of dihydrotestosterone on hair follicles leading to miniaturization

Alopecia areata

Equally affects both sexes, with usual onset before age 30Most common areas of hair loss are scalp and beard regionsRound areas of complete hair loss with retained follicular ostiaExclamation point hairs found at the edges of expanding areas of hair loss are a hallmark signCaused by autoimmune destruction of hair follicles involving cell-based and humoral immunity

Telogen effluvium

Acute telogen effluvium is characterized by diffuse scalp hair loss lasting ,6 mo, whereas the duration is .6 mofor chronic telogen effluvium

Women between ages 30 to 60 are most commonly affectedA stressor event may or may not be present, usually occurring 2–4 mo before onset of hair shedding20%–50% of scalp hairs transition prematurely to telogen phase and are shed with normal hair shafts

Anagen effluvium

Diffuse hair loss characterized by hair breakage during anagen phaseClassic causative agents are radiation therapy and cancer chemotherapyAffects 80%–90% of scalp hairs with onset within 1–4 wk of exposureNarrowing, fractured hair shafts constitute a characteristic sign

Loose anagen syndrome

Typical patient is a blond female aged 2–5 who presents with diffuse hair loss and short, dull hair6:1 Female to male ratio among the patient population, which includes adults and dark-haired individuals

as wellGreater susceptibility to hair breakage caused by premature keratinization of the inner root sheath, causing

impaired adhesion with the hair shaft cuticleShorter anagen phase leads to reduced hair length

Trichotillomania

Patients experience an irresistible urge to pull out their own hair despite negative impacts to their occupationaland social function

Childhood trichotillomania affects more boys than girls and resolves spontaneouslyAdult trichotillomania affects women much more frequently than menOften comorbid with mood or anxiety disordersShort, fractured hairs distributed sparsely and irregularly in affected areas

Traction alopecia

Results from tension applied to hair for a prolonged period of time, from hairstyles such as tight ponytails andbraids, as well as hair-styling devices

Areas under greatest pressure are most affected, usually scalp marginsEspecially common among African-American females because of their association with certain hairstylesTypically hair loss is transient; scarring or inflammation may be observed

Continued


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development (Watt and Collins 2008). A secondpathway that has been found to be elevated inbalding scalp involves prostaglandin D2 syn-thase, as well as its product, prostaglandin D2

(PGD2). PGD2 has been shown in humans andin mice to inhibit hair growth, an effect thatrequires the expression of PGD2 receptor G pro-tein-coupled receptor 44 (Garza et al. 2012).

After these early signals, the DP cells foundin areas of AGA are known to enter senescenceprematurely, and this phenomenon has beenlinked to the expression of cell cycle regulatorsp16INK4a/pRb (Bahta et al. 2008). After all ofthese events, an ongoing question has been thestatus of the hair follicle stem cell compartmentin AGA. In a comparison of scalp areas with orwithout hair loss, investigators demonstrated arelative lack of hair follicle progenitor cells (earlystem cell progeny) in balding areas, althoughnumbers of parental stem cells remained un-changed. Impaired transition from stem cell toprogenitor cell may contribute to the reducedhair follicle size observed in AGA patients (Garzaet al. 2011). This novel research represents po-tential areas for advancement in therapy.

Also noteworthy are the recent findings ingenetic mapping of AGA. Numerous studieshave already identified polymorphisms in theX-linked androgen receptor gene that may in-crease susceptibility for AGA (Zhuo et al. 2012).According to a study conducted on individualsin Sardinia, AGA is also associated with theX-linked gene EDA2R encoding ectodysplasinA2 receptor, independent of linkage disequi-librium (Prodi et al. 2008). An association ofAGAwith EDA2R would suggest an overlappingdefect of hair growth inhibition in ectodermaldysplasia patients with mutations in this path-way (Mikkola and Thesleff 2003). Improvedunderstanding of the genetic basis for AGAwill elucidate the underlying molecular mecha-nisms that give rise to the condition.

Alopecia Areata


Alopecia areata (AA) is a nonscarring form ofhair loss that has a lifetime prevalence of ap-proximately 2%. Men and women are equally

Table 1. Continued

Cicatricial alopecias

Chronic cutaneous lupus erythematosus

Scaly, erythematous plaques with well-demarcated borders that eventually atrophy, found on sun-exposed areasincluding scalp

Most common form is discoid lupus erythematosus, accounting for 50%–85% of all casesAffects more women than men, usually between ages 20–45Associated with carpet tack sign, describing follicular spikes on the undersurfaceCases among African-Americans are often more severe

Lichen planopilaris

Considered to be a variant form of lichen planusClassic lesions are smooth white areas with absent follicle ostia and central scarring; edges are characterized by

erythema and scaling around hair folliclesMostly affects adult women at the crown and parietal areas of the scalpDue to autoimmune attack on hair follicles mediated by T lymphocytes

Central centrifugal cicatricial alopecia

Scarring hair loss that usually begins at the crown and expands outward to affect the entire scalpMiddle-aged African-American females are most commonly affected; individuals of other races rarely present

with this conditionMay be associated with chemicals and pressure applied to hairLymphocyte-rich infiltrates observed at edges of balding lesions with signs of inflammation



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affected, with onset of symptoms occurringmost commonly before age 30. The conditionhas a hereditary component—20% of patientspossess at least one first-degree relative withAA. Comorbidities in select patients includeautoimmune disorders such as thyroid disease,vitiligo, and atopy. Indeed, hair loss in AA isunderstood to occur because of T-lympho-cyte-mediated autoimmune attack on hair fol-licles in anagen phase. Humoral immunity isalso involved through hair follicle autoantibod-ies. The scalp and beard regions are most sus-ceptible, but other areas of the body can beaffected as well. Alopecia on the scalp manifestsas smooth, round patches of complete hair shaftloss, but with retained follicular openings. Atthe edges of expanding areas, exclamation pointhairs can be found. These are short, fragmentedhairs that are thinner at the proximal end andconsidered a hallmark of AA. Hair loss may pro-gress to alopecia totalis, meaning complete bald-ing at the scalp, or to alopecia universalis, de-scribing loss of all hair on the body. Severe casesare associated with nail pitting (Habif 2010;Gilhar et al. 2012; Otberg and Shapiro 2012).

For 80% of AA patients, hair regrowsspontaneously within a period of 1 yr since on-set. Management for the condition is generallyfocused on modulating the autoimmune re-sponse. Corticosteroid injections into affectedareas serve as a first-line approach for whenhair loss affects ,50% of the scalp. Topical cor-ticosteroids are widely used and exert greaterbenefits when used with occlusive dressings.For extensive alopecia, inducing contact derma-titis by applying allergens, a procedure known astopical immunotherapy, provides benefit withsome patients and oral corticosteroids representan additional option. Other measures consistof minoxidil and the experimental use of novelimmunosuppressive biologic drugs, althoughthe latter option has yet to show significant ben-efit in clinical trials (Strober et al. 2005, 2009;Price et al. 2008). Psoralen plus UVA therapyis less commonly used because of inadequateefficacy and associated harms of photoagingand photocarcinogenesis. Nonpharmacologicaloptions include hairpieces and temporary tat-tooing, which helps patients with loss of eye-

brow hair (Habif 2010; Gilhar et al. 2012; Otbergand Shapiro 2012).


Perhaps the most important breakthrough inthe last several years in the field of AA is a ge-nome-wide association study that uncovered139 single-nucleotide polymorphisms relatedto the condition. Implicated genes possessedroles in acquired immunity, including cytotoxicT-lymphocyte-associated antigen 4 (CTLA4),interleukin (IL)-2/IL-21, IL-2 receptor A, andEos. The human leukocyte antigen region wasalso involved. Associations with hair folliclegenes PRDX5 and STX17 were found as well.Especially interesting was the finding that thecytomegalovirus UL16-binding protein (ULBP)gene cluster yielded a strong correlation, the firsttime the region has been linked to an autoim-mune disorder. ULBPs play a role as ligands forthe natural killer (NK) cell receptor NKG2D andthus are part of innate immunity. Further in-vestigation demonstrated that ULBP is overex-pressed in affected scalp areas in AA patients(Petukhova et al. 2010). The study has shed freshinsight into the genetics behind AA pathogene-sis, which likely involves both innate and adap-tive immunity.

There is also evidence that highlights theinvolvement of NK cells. Hair follicle epithe-lium in AA patches had markedly elevatednumbers of NK cells, whereas few were observedaround normal hair follicle epithelium, whichexpresses significant levels of NK cell inhibitormacrophage migration inhibitory factor (Itoet al. 2008). Another study that explored filag-grin (FLG) gene mutations did not detect a sig-nificant relationship between FLG mutationsand AA per se. However, the mutations werecorrelated with higher incidence of atopic der-matitis in AA patients, and among these com-orbid patients the prognosis of AA was worse(Betz et al. 2007).

The importance of neuropeptides and thelocal hormonal axis is an ongoing area of in-quiry regarding hair follicle biology and AA.The C3H/HeJ mouse AA model has yieldednew information in recent years. When AA



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mice were subjected to stress, they showed en-hanced hypothalamic-pituitary-adrenal (HPA)axis activity compared with normal mice. Theinvestigators postulate that HPA activity maybe modified in the context of AA (Zhang et al.2009). In the same mouse model, researchersdemonstrated that the neuropeptide substanceP might regulate inflammatory response inAA (Siebenhaar et al. 2007). These studies mayhelp unravel additional pathways underlyingthe disease.

DIFFUSE HAIR LOSS

Telogen Effluvium


Diffuse hair loss, in contrast to AGA and AA,affects the scalp area uniformly. The most com-mon type is telogen effluvium, which is classi-fied as either acute or chronic. Acute telogeneffluvium (ATE) involves hair shedding thatpersists ,6 mo. There is usually a trigger thatoccurs 2–4 mo before onset of hair loss. Thecause may be endocrine, in the event of child-birth and hyper/hypothyroidism; nutritional,encompassing crash diets and vitamin A ex-cess; drug-related, most notably anticoagulantsand b-blockers; and stress. Febrile illnesses andmalignancies are often implicated as well. Thestressor event induces between 20%–50% ofscalp hairs to transition to and remain in telogenphase for �3 mo until they are shed. Hair shaftsremain normal. The process itself is physiolog-ical; the abnormality lies in the large number ofhairs that are simultaneously affected, as regu-larly only 5%–10% of hairs are in telogen phase.Patients present suddenly with diffuse hair loss,although complete balding does not occur. Re-moval of the hair stressor allows for regrowthand recovery of the normal distribution of telo-gen hairs over several months. In chronic telo-gen effluvium (CTE), hair loss persists longerthan 6 mo. Although ATE can emerge at any age,CTE generally affects women between 30 to 60yr of age. Five-percent minoxidil solution isused as a treatment of CTE (Habif 2010; Otbergand Shapiro 2012).


Stress has traditionally been linked to the devel-opment of telogen effluvium. In particular, thestress-associated factors substance P and nervegrowth factor (NGF) have been shown to de-crease hair growth and promote transition tocatagen phase (Peters et al. 2006). The two fac-tors are interrelated, as substance P up-regulatesthe expression of NGF and its catagen-associ-ated receptor. Moreover, substance P depriveshair follicles of their immune-privileged status(Peters et al. 2007). Hair follicles have beenshown to possess a local stress response systemakin to the HPA axis, and influences on hairfollicle growth by levels of thyroid hormonesT3 and T4 have also been discussed (Ito et al.2005; van Beek et al. 2008). Further research isrequired for a comprehensive understanding oftelogen effluvium pathogenesis.

Anagen Effluvium


Anagen effluvium is another example of diffusehair loss. Instead of hair shedding, however, asoccurs in telogen effluvium, the abnormal hairsbreak off in anagen effluvium. Radiation thera-py and cancer chemotherapy are widely under-stood to be the precipitating factors for this con-dition, although poisons such as arsenic andthallium are known causes as well. Cells withhigh rates of mitotic division, like the matrixand cortex cells of hair follicles, are most suscep-tible to damage. Symptoms present more quick-ly and dramatically than in telogen effluvium.Hair loss becomes apparent within 1 to 4 wkafter exposure to the causative agent, and ap-proximately 80%–90% of scalp hairs are affect-ed. Damage to the hair shaft leads to narrowingand fracture without bulbs. Hair growth ordi-narily recovers after �4 mo following termina-tion of chemotherapy, although irreversible hairloss has been reported in cases of multiagentchemotherapeutic regimens (Habif 2010; Ot-berg and Shapiro 2012).

Much investigation has been undertaken re-garding the management of anagen effluviumcaused by chemotherapeutic agents. The most



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promising pharmacologic interventions havebeen minoxidil and AS101, although their ben-efits were restricted to improvement of symp-toms or disease duration and not applicableto prevention (Wang et al. 2006). Scalp coolingmay be effective for some patients and is toler-ated well in most cases (Grevelman and Breed2005). Calcipotriol and topical calcitriol havefailed to demonstrate preventative or modu-lating effects in patients (Hidalgo et al. 1999;Bleiker et al. 2005). Multiple avenues are openfor investigation to improve treatment optionsfor alopecia in cancer patients.

Loose Anagen Syndrome


The classic loose anagen syndrome (LAS) pa-tient is a blond girl aged 2 to 5 who experiencesdiffuse hair loss and whose unruly, relativelyshort hair requires few haircuts (Price andGummer 1989). The patient profile can deviatefrom this standard pattern, as LAS has also beenobserved in males, although the ratio of femalesto males among the patient population is 6 to 1.Adults as well as individuals with dark hair canbe affected. Cases can be familial or sporadic innature. The condition is understood to occurbecause of premature keratinization of the innerroot sheath of the hair follicle, thereby reducingits adhesion with the hair shaft cuticle. The re-sulting hair is at risk for breakage and pain isabsent. The duration of anagen phase is short-ened, explaining the reduced hair length. Hairgrows sparsely, characterized by dull texture. Notreatment is available for LAS, but prognosis isgood; most patients’ symptoms lessen with age(Habif 2010; Otberg and Shapiro 2012).


LAS occasionally presents within the context ofgenetic disorders such as Noonan’s syndrome,coloboma, and hypohidrotic ectodermal dys-plasia (Habif 2010). According to recent re-search, mutation in SHOC2 (Soc-2 suppressorof clear homolog), a leucine-rich repeat-con-taining protein, causes Noonan-like syndromewith loose anagen hair. The researchers postu-

late that SHOC2 may play a part in regulatingthe growth of epithelial hair follicle stem cellsand their derivatives (Cordeddu et al. 2009).Progress is underway toward uncovering themolecular background behind LAS.

TRAUMATIC HAIR LOSS

Trichotillomania


Trichotillomania describes chronic, impulsivehair pulling that causes alopecia. 0.6% to 13%of the population is estimated to be afflicted withthis condition. More boys than girls are affectedby childhood trichotillomania, which normal-ly resolves spontaneously. Among adults, manymore women are affected than men. Patients ex-perience an urge that they gratify by pulling outhair, engaging in this task for up to 3 h per day.They are unable to resist despite negative impactsto their work and or social lives. Trichotilloma-nia is often comorbid with mood or anxiety dis-orders, and greater incidence of this condition isreported in patients with psychological illness(Habif 2010; Otberg and Shapiro 2012).

Although the frontoparietal area of thescalp is most frequently affected based on easeof access, other regions of the scalp and face arealso susceptible. Affected patches are character-ized by sparse, irregularly distributed growthsof short, fractured hairs. None of the areaswill demonstrate complete lack of hair shafts,a distinction between trichotillomania and AA(Habif 2010; Otberg and Shapiro 2012).

Provided the patient is stable psychological-ly, the problem can resolve following discussionwith a physician. Treatment becomes more in-volved for persistent or severe cases. Among thevarious options, behavioral therapy has beendetermined to yield greater benefit than clomi-pramine, and the efficacy of selective serotoninreuptake inhibitors may be equivalent to place-bo. Support for the patient is important in con-fronting this difficult condition (Habif 2010).


An interesting development in the field oftrichotillomania research is the discovery that



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Hoxb8 mutant mice showed compulsive hair-pulling similar to that observed in humans.Mutation in this gene impairs bone-marrow-derived microglia in the brain, causing hair re-moval and intense grooming (Chen et al. 2010).The study represents an important step forwardtoward comprehension of the molecular work-ings behind trichotillomania.

Traction Alopecia


Traction alopecia results from tension appliedpersistently to hair, such as in the case of certainhairstyles including tight ponytails and braids,and also from hair styling devices like hot rollersand hair straighteners. Affected areas corre-spond to areas under the greatest amounts ofpressure, and usually hair loss occurs at scalpmargins. Traction alopecia is usually transient,although scarring or signs of inflammation maybe observed. With early detection and manage-ment, reversal of symptoms generally occurswithin a few months. Because of the associationbetween specific hairstyles and cultures, certainpopulations are especially vulnerable to this con-dition; for instance, braiding and weaving in Af-rican-American females increase the prevalenceof traction alopecia in this group (Callenderet al.2004; Habif 2010; Otberg and Shapiro 2012).

To prevent permanent alopecia, patients areadvised to switch to more relaxed hairstyles assoon as possible to relieve the stress on theirhair. Pharmacological treatments include mi-noxidil, which has been beneficial for somepatients, as well as antibiotics and corticoste-roids in the event of folliculitis or inflammation,respectively. Surgical intervention remains anoption for patients with advanced hair loss(Callender et al. 2004).

CICATRICIAL ALOPECIAS

Chronic Cutaneous Lupus Erythematosus


Chronic cutaneous lupus erythematosus(CCLE) is a progressive disease of the skin thatmanifests as scaly, erythematous plaques with

well-demarcated borders. These may eventuallybecome atrophic, and patients often experiencepruritus and tenderness at the scalp. Sun-ex-posed areas like the scalp, face, and ears aremost susceptible. The condition is usually con-fined to the skin but coincides with systemiclupus erythematosus (SLE) in some patients(Hordinsky 2008). CCLE has various forms,the most common of which is discoid lupuserythematosus (DLE), accounting for approx-imately 50%–85% of all cases. DLE is mostfrequently observed in individuals aged 20 to45, with more women than men affected. Casesamong African-Americans are reportedly moresevere than for other races. DLE is distinguishedfrom other cicatricial alopecias in that erythe-ma, scaling, and changes in pigmentation canbe dramatic and feature most prominently atthe centers of lesions rather than at the edges.The “carpet tack” sign is associated with DLE,describing scales that show follicular spikes onthe undersurface. Follicular plugging and dila-tion of follicular orifices occur as lesions age,but these signs gradually fade as plaques atro-phy, leaving smooth scars. DLE can be localizedor generalized (Hordinsky 2008; Wolff et al.2009; Habif 2010).

Routine application of sunscreens with SPFmore than 30 is important for prevention ofDLE. Topical and intralesional corticosteroids,calcineurin inhibitors, antimalarials, and reti-noids are some of the available options fortreatment. For DLE with more extensive in-volvement, the choices include cyclosporine,hydroxychloroquine sulfate, retinoids, and aza-thioprine (Hordinsky 2008; Habif 2010). Arecent retrospective cohort study examinedhydroxychloroquine efficacy and verified clini-cal response to the drug in the majority ofpatients. Lack of response was correlated withgeneralized disease and comorbidity with SLE.These results offer factors to consider in pre-dicting response to hydroxychloroquine (Wahieet al. 2011).


DLE pathophysiology still remains poorly un-derstood. T-lymphocyte infiltration has long



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been predicted to contribute to the condition.In particular, autoreactive CD8þT lymphocytesand type I interferons have been linked to scar-ring in DLE (Hordinsky 2008). More recently,the type III interferon IFN-l and its receptorwere discovered to be overexpressed in the epi-dermis of DLE lesions. Indeed, human keratin-ocytes exposed to IFN-l1 increased productionof proinflammatory cytokines associated withthe development of CLE lesions. Thus, type IIIinterferons possibly contribute to DLE patho-genesis (Zahn et al. 2011).

Additionally, the damage-associated molec-ular pattern molecules myeloid-related protein-8 (Mrp8) and Mrp14 have been shown to play arole in this process. Mrp8 and Mrp14 are up-regulated in epidermal cells from the lesions ofpatients with cutaneous lupus erythematosus,and the expression of these genes is involvedin the induction of self-reactive cytotoxic Tlymphocytes. Furthermore, Mrp8 and Mrp14play roles in the toll-like receptor 4 signalingpathway, which stimulates expression of in-terleukin-17 (Loser et al. 2010). Another studyinvestigated Ro52, an E3 ubiquitin ligase; auto-antibodies targeting Ro52 have previously beencorrelated with cutaneous lupus erythemato-sus. Levels of Ro52 expressed by epidermal cellsfrom CCLE lesions were elevated, and UV radi-ation increased Ro52 levels. The investigatorssuggest that sun exposure stimulates Ro52 ex-pression, triggering the production of Ro52autoantibodies and the development of skinlesions (Oke et al. 2009). These studies shedinteresting insight on the mechanisms of DLEpathogenesis and provide opportunities for thedevelopment of novel therapies.

Lichen Planopilaris


Lichen planopilaris (LPP), also known asfollicular lichen planus of the scalp, is a rarecicatricial alopecia that occurs because of auto-immune attack of hair follicles, mediated bycell-based immunity. LPP is considered a vari-ant form of lichen planus, an inflammatory dis-order of skin and mucous membranes caused

by keratinocyte-targeting autoreactive T lym-phocytes. The exact cause remains unclear forlichen planus and LPP. However, risk factorshave been identified, including viral infections(such as hepatitis C virus), contact with metalslike gold, and use of certain medications such asthiazide diuretics and quinine (Kang et al. 2008;Otberg and Shapiro 2012).

Adult women make up the majority of theLPP patient population. The crown and parietalareas of the scalp are most commonly affected,and multiple focal lesions may gradually fuse toform extensive regions of alopecia. Classic LPPlesions typically have a smooth white appear-ance with central scarring and absence of follicleopenings. The edges show erythema and scalingaround hair follicles. In addition to increasedhair loss, patients may experience burning, pru-ritus, and stinging. Aside from classic LPP, theother subtypes of LPP are frontal fibrosingalopecia (FFA) and Graham-Little syndrome.FFA is seen mostly in postmenopausal women,presenting as a band-like pattern of hair losspredominantly at the frontal hairline. Eyebrowinvolvement is common. Graham-Little syn-drome, on the other hand, consists of the fol-lowing triad: scalp cicatricial alopecia, lichenplanus spinulosus (extensive patches of fol-licular keratotic papules), and noncicatricial al-opecia at the pubic and axillary regions (Kanget al. 2008; Habif 2010).

Intralesional corticosteroid injections con-stitute first-line therapy for LPP that affects,10% of the scalp. These can be combinedwith topical corticosteroids for further symp-tom relief. In the case of fulminant LPP, oralcorticosteroids are prescribed. Hydroxychloro-quine therapy is geared toward patients with.10% of their scalp affected by LPP or whodo not respond to corticosteroids. For patientswho do not improve after treatment with corti-costeroids or hydroxychloroquine after 3 to 6mo, immunomodulating agents cyclosporineand mycophenolate mofetil serve as options.Adding topical minoxidil to the regimen willaid in preventing hair loss. Other pharmacol-ogical approaches that have been tested andshowed some benefit include thalidomide, tet-racycline, dapsone, and isotretinoin. Surgical



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alternatives like hair transplants are also avail-able (Cevasco et al. 2007; Kang et al. 2008; Habif2010).


Significant advances have been made in recentyears toward understanding LPP etiology. Re-searchers have managed to highlight associa-tions between specific genes and LPP. In onestudy, gene expression patterns of normal scalpand LPP lesions were compared via microar-ray. Scalp areas affected by LPP were character-ized by diminished expression of genes involvedin peroxisome production and lipid meta-bolism. Further bioinformatic analysis iden-tified reduced expression of the transcriptionfactor peroxisome proliferator-activated recep-tor g (PPARg). The researchers then generatedPPARg knockout mice in which the gene muta-tion is targeted to follicular stem cells expressingKRT15. These mice developed cicatricial alope-ciawith pruritus, resembling the clinical presen-tation of LPP patients. Thus, PPARg representsa novel target in LPP therapy (Karnik et al.2009). The evidence regarding PPARg is corrob-orated by findings in defolliculated or Gsdma3(gasdermin A3) mutant mice. Gsdma3 is a geneinvolved in regulating epidermal differentia-tion, and the mutant mice show signs of cicatri-cial alopecia (Lunny et al. 2005). There is de-creased PPARg expression in Gsdma3 mutantmice such that these mice may be used to inves-tigate therapy innovations (Ruge et al. 2011).PPARg agonists have been tried for LPP treat-ment with mixed to moderate results (Karniket al. 2009; Baibergenova and Walsh 2012).

Furthermore, microarray results demon-strated an increased expression of the aryl hy-drocarbon receptor (AhR) in LPP lesions (Kar-nik et al. 2009). AhR is a xenobiotic receptor (areceptor for foreign chemicals) that has beenfound to reduce PPARg expression on exposureto dioxin-like substances (Hanlon et al. 2003;Cimafranca et al. 2004). Dioxins accumulatein animals exposed to environmental contami-nants, and through consumption of their meat,humans are exposed to dioxin (Mozaffarian andRimm 2006). Thus, there may be a role for for-

eign toxins, mediated by the AhR pathway, inthe pathogenesis of LPP.

Central Centrifugal Cicatricial Alopecia


The North American Hair Research Societydefines central centrifugal cicatricial alopecia(CCCA) as the scarring hair loss typically oc-curring at the crown that mostly affects Afri-can-American females. Synonyms include hot-comb alopecia, as the condition was originallyknown, and follicular degeneration syndrome.The classic patient is a middle-aged African-American woman, although the condition hasbeen observed in younger women as well asmen. Individuals of other races are rarely af-fected. Hair loss usually begins at the vertexand expands outward symmetrically, eventuallyaffecting the entire scalp. The active phase, dur-ing which inflammatory attacks on hair folliclespersist, lasts for several years but is general-ly self-limiting. Lymphocytes predominate inthe infiltrates at the edge of balding lesionswith signs of inflammation (Whiting and Olsen2008; Otberg and Shapiro 2012).

The cause of CCCA remains unclear. In ac-cordance with its former name (hot-comb alo-pecia), the condition was originally believed topresent following use of hot combs, the effectsof which were exacerbated by chemicals andapplication of physical pressure. However, giventhat a majority of African-American womenhave used hair relaxers, but ,6% show signsof extensive central hair loss, it is likely thathairstyling methods are not the only cause(Olsen et al. 2011). Autoimmune and geneticcomponents are under consideration as well.Aside from these, infections and associationwith female pattern hair loss have been namedas contributing factors. There remains muchopportunity for research in this area (Whitingand Olsen 2008).

To manage CCCA, patients are advised torefrain as much as possible from inflicting dam-age to their scalp via various hairstyling meth-ods. These include greasing the scalp, using hotcombs and relaxers, and wearing taxing styles



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like cornrows and tight braids. Maintaining anatural hairstyle for at least a temporary periodmay allow for some recovery by the patient’shair and scalp. As for pharmacological ap-proaches, the common objective is to reduceinflammation. Topical corticosteroids and im-munomodulators (tacrolimus and pimecroli-mus), oral antibiotics like tetracycline, intrale-sional injections of corticosteroids, and shortcourses of oral corticosteroids are availableoptions for patients. Topical minoxidil may begiven to encourage hair growth, and hairpiecesare a nonpharmacological alternative (Whitingand Olsen 2008).


It has been discussed previously in this sectionthat PPARg dysfunction may contribute to de-velopment of LPP. For CCCA, a coactivator ofPPARg is reportedly down-regulated (Price andMirmirani 2011). Foreign toxins such as diox-ins, a class of chemicals mentioned earlier withregard to their suppression of PPARg via theAhR, may also contribute to the pathogenesisof CCCA, although more investigation is neces-sary to confirm this claim.

Researchers have additionally examined therole of cytokeratin 75 (K75). Premature desqua-mation of the inner root sheath (PDIRS) is rec-ognized as a histological marker for CCCA, andK75 is expressed by the hair follicle companionlayer, which serves as an interface for the des-quamation process. Analyses of normal scalpand CCCA-affected scalp revealed that K75 ex-pression diminishes during the initial stages ofinner root sheath desquamation and eventuallydisappears (Sperling et al. 2010). Although theinvestigators of the study do not predict a directrole for K75 in CCCA pathogenesis, its associa-tion with PDIRS presents prospects for furtherinquiry.

Yet another path for inquiry in CCCA re-search concerns the sebaceous gland. Inflam-mation and loss of sebaceous glands were fre-quently observed as early findings in primarycicatricial alopecias, including CCCA (Al-Zaidet al. 2011). The inflammatory activity of sebummay therefore be implicated in CCCA patho-

physiology, with much opportunity for researchin this area.

FUTURE RESEARCH DIRECTIONS

Various approaches in the realm of alopeciaresearch are continuing to determine the mech-anisms behind disease processes. Numeroustransgenic mice have already contributed in-valuable knowledge to the field, as discussedearlier in this article. To create them is laborintensive with a high risk for failure. When suc-cessful, however, the phenotypes in the trans-genic mice may have striking overlap to humanpathology and provide powerful support for theinvolvement of the gene in question. These an-imals can then serve as models for investigationof novel therapies. In the most effective ex-amples of productive research, these biologicmodels are paired with in vitro assays to betterdefine mechanism. Although these do not dem-onstrate clinical presentations as elegantly asknockout mice, they allow for far more sim-plification and control. A third arena for re-search that often can precede the previous twoare for exploring genetic questions on eithersmall-scale expression screens or larger-scale,genome-wide association studies. Overall, it isclear that the domain of alopecia research willbenefit from combining these three avenues.

Basic and applied research strategies in hairfollicle biology are also describing potential newavenues for treatment of hair loss conditionsand methods to induce new hair growth. Fromcareful promotion of Sonic hedgehog signaling(Callahan and Oro 2001; Paladini et al. 2005) tostimulating Wnt signaling (Gat et al. 1998),clear targets exist to manipulate hair folliclecycling and/or growth. Modulating prostaglan-dins represents another exciting new directionfor therapeutics (Wolf et al. 2003). Future re-search will explore the use of cellular therapyfor alopecia (Stenn and Cotsarelis 2005), suchas autologous dermal papillae cells to induce ahair follicle. Additionally, induced pluripotentstem cells might be coaxed into hair follicle lin-eages to promote hair growth (Itoh et al. 2011;Veraitch et al. 2012). Therapies involving RNAsilencing are also among the emerging possibil-



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ities for treatment of alopecias (Dugour et al.2009). Indeed, fundamental shifts in researchfrom describing pathogenesis defects to devel-oping interventions to treat those defects areunderway (Uitto et al. 2012). It is an excitingtime in the field of hair research—much prog-ress has been made, and there is much oppor-tunity for further advances.

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