investigative guidelines for alopecia areata

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Investigative guidelines foralopecia areatadth_1415 311..319

Elise A. OlsenDepartment of Dermatology and Medicine (Oncology), Duke University

Medical Center, Durham, North Carolina

ABSTRACT: The reported efficacy of various treatments for alopecia is difficult to compare based on ageneral lack of consideration in case reports/series and clinical trials of the spontaneous regrowth orbaseline prognostic factors seen in alopecia areata and a general lack of quantification of hair growth.This report will give both the investigator and clinician guidelines for clinical trial design that will takeinto account variables known to effect efficacy results such as baseline severity, pattern, and duration of

hair loss, age of the subject, and concomitant conditions that may impact on potential regrowth.Reliable methods of assessment of efficacy and response criteria that will enable direct comparison ofresults between agents will also be discussed.

KEYWORDS: alopecia, alopecia areata, investigative guidelines

Introduction

Alopecia areata is an enigmatic disease. Recentgenetic detective work has suggested its relation-ship to other autoimmune diseases including type Idiabetes, and rheumatoid arthritis (1), disordersthat unlike alopecia areata, have constant pheno-typic expression. Alopecia areata is unique in thatits clinical manifestations (hair loss, nail effects) areneither constant nor cyclic nor expressed in all rel-evant cells at any one time but rather are expressedsporadically. The first presentation of hair loss maybegin at any age, can involve scalp and/or bodyhair, and can be either discrete patches or wide-spread rapid total hair loss. Regrowth may occur

spontaneously months to years after onset of thehair loss or the hair loss may persist indefinitelydespite therapeutic interventions. Onset ininfancy/early childhood, the presence of atopy andthe total loss of scalp hair appear to be factors thatindependently encourage persistence of hair lossand/or recurrent episodes of hair loss.

To date, there is no FDA-approved treatment foralopecia areata and evidence-based efficacy data

are largely lacking, much of this related to the manyvariables noted above that are impossible to controlfor in alopecia areata. The literature on therapy ofalopecia areata primarily consists of small uncon-trolled studies whose results cannot be directlycompared because either the endpoints are poorlydefined or nonquantitative or the site and severityof hair loss at baseline is not taken into account.This paper reviews the methodology necessary tonot only conduct standardized placebo-controlledclinical trials but to enable determination of com-parative efficacy of various therapeutic agents inalopecia areata tested under different study proto-

cols and/or at different sites. Recommendations forstudy design take into account the various typesand amount of hair loss, the potential for sponta-neous regrowth, and the known negative prognos-tic factors in alopecia areata.

Study design

Up until recently, reports of efficacy of treatmentin alopecia areata have been largely fromuncontrolled, small cohort, case report series. The

Address correspondence and reprint requests to: Elise Olsen,

MD, Dermatology and Oncology, Duke University Medical

Center, Durham, NC 27110, or email: [email protected].

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Printed in the United States All rights reserved 2011 Wiley Periodicals, Inc.

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half-head study design introduced the controlledclinical trial to the assessment of efficacy oftreatments for alopecia areata. More recently,placebo-controlled, parallel group studies havebeen successfully conducted in alopecia areata.

Half-head studies

In these studies, a topical medication is applied tothe alopecic areas on one half of the scalp and theareas of alopecia on the other side of the scalp areleft untreated as the control. The reliability of thisdesign depends on the amount of hair loss beingsimilar on the treated and untreated sides of thescalp and is best when there is extensive versusminor hair loss on both sides of the scalp. The effi-cacy of the study drug is assumed when terminalhair growth occurs only on the treated side andspontaneous regrowth is generally assumed whenhair growth occurs on both treated and untreatedsides (FIG. 1). This method has been provenparticularly useful in determining the efficacyof topical steroids or topical sensitizers, the latter

when applied by the study investigator. Forexample, Happle et al. and Wiseman et al. usedthis method to determine the efficacy of topicaldiphencyprone (DPCP) in alopecia areata (2, 3). Ifterminal hair growth was shown to occur only, or toa greater extent, on the side of the topical DPCP

application, the response was considered specificto the drug and the treatment was then extended toboth sides of the scalp to assess overall efficacy ofthe treatment. The University of British Columbiagroup also utilized the half-head study designto prove the ineffectiveness of topical nitrogen

mustard in alopecia areata: only 1/6 showed a uni-lateral response to therapy in a 16-week study (4).Using the half-head study model, Kaplan andOlsen proved that topical 5-fluorouracil is ineffec-tive in alopecia areata (5).

The main thrust for doing such half-headstudies has been the ease of using the patient ashis/her own control. While this may be a reason-able approach for topical sensitizers, which areapplied by the investigator and which have only alocal effect, there are problems with using thismethod with a preparation that the patient mustapply or topical medications that could have an

effect beyond the area of drug application. Aresponse seen bilaterally when the patient isinstructed to only apply the medication to one sideof the scalp could be secondary to either sponta-neous regrowth, inadvertent or purposeful applica-tion on both sides of the scalp by the patient, or asystemic effect of the topical medication. Surpris-ingly, the half-head studies of topical clobetasolunder occlusion in patients with alopecia totalis oruniversalis in which one could envision a systemiceffect of the corticosteroid occurring, showed hairgrowth on both sides only in 1/28 patients (6).

However, Talpur and Duvic felt that the responsesseen on the untreated side of the scalp in a study in

which patients self-applied topical bexarotene,could possibly be secondary to either systemicabsorption or diffusion of the study drug (7).

To use the half-head study design for clinicaltrials of alopecia areata, it is best to have the inves-tigator apply the study drug and to attribute effi-cacy to the hair growth promoter only in thosepatients in which hair growth is limited to thetreated side.

Double-blind, placebo-controlled parallelgroup studies

This type of study can be used to assess the efficacyof topical, intralesional or systemic agents inalopecia areata. In this study design, patients arematched for as many variables as seem relevant(see discussion below) and are randomized toreceive active drug or placebo. Active and placeboagents, applied topically or injected intralesionally,are to be used on all alopecic areas rather than justthose on one side of the scalp. This study design

FIG. 1. Patient treated on half head only with topical clobe-tasol ointment with occlusion (reprinted with permission).

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requires many more patients than the half-headstudy design but it removes any potential for mis-application of study drug by patients and allowsthe investigator to be blinded as to treatment whenmaking an assessment. It also is the only type ofplacebo-controlled study that can reliably be per-

formed with a systemic agent or with any externallydirected agent that may have a systemic effect.

Active-control parallel group studies

In the future, performing active-control studiesmay become important in alopecia areata, particu-larly if a single gold standard treatment is identifiedand has predictable results. At this point in time,the benchmark treatment is likely systemic corti-costeroids but there is not general acceptanceof this as first line therapy in alopecia areata.However, even if one does carry out an active-

control study, a third placebo arm is recommendeddue to the potential for spontaneous remission inalopecia areata. In two placebo-controlled clinicaltrials of alopecia areata, the percentage of sponta-neous regrowth at 3 months varied depending onbaseline hair growth and the definition of regrowthutilized in the analysis: in patients with 50% hairloss at baseline, 8% (2/25) on placebo had at least25% regrowth (8) and in patients who did not haveany minimal criteria for baseline hair loss severity,28.5% (4/14) on placebo had 5099% regrowth (9).

Cross-over studies

A study design that has patients randomized toeither placebo or active drug and then, after a setperiod of time, crossed over to the alternate treat-ment, has certain positive attributes. This type ofstudy allows the patient assigned to placebo ini-tially to act as his/her own control in the placeboperiod and then insures that all patients receiveactive drug, an important point for patient reten-tion in a clinical trial. The value to the patientsassigned initially to active drug is less clear since ifthey are having a positive response to study drug,they will have an effective treatment discontinuedbefore full efficacy is achieved and likely resump-tion of further hair loss. And for the investigator,there are two potential problems to patients begin-ning with active drug before crossing over toplacebo: it will be impossible to ferret out sponta-neous hair growth versus drug induced hair growthduring the active treatment phase and the activeagent will most assuredly have an effect on theresults in the placebo phase following it.

However, a placebo-crossover phase added onto a parallel treatment design would preserve the

placebo comparative phase upfront, insure allpatients of getting active drug and insure anextended treatment period for those patients ini-tially randomized to the active treatment group.However, the only part of such a study that is con-trolled is while some patients remain on placebo

and given the increasing potential for spontaneousregrowth over time, the time on placebo should beas long as necessary to fully assess the potentialregrowth of the study drug.

Duration of study

This is an important aspect of study design.Clearly, intralesional and systemic steroids areable to initiate hair growth more rapidly (12months) than topical corticosteroids (34 months)(Olsen, personal communication; (10)). Ultravio-

let light has been reported to take an average of 3months for a response (11) and psoralen plus UVA(PUVA) an average of 30 sessions before vellushair appears, 5080 sessions before full regrowth(12). Topical sensitizers generally take 3 months toshow initial hair growth but 1224 months for themaximum response (3). The study duration forany particular clinical trial should take intoaccount the time for initiation of hair growth

with that particular agent and whether the objec-tive of the study includes determining whetherfull regrowth can be achieved. For example, in the

topical 5-fluorouracil trial conducted at DukeUniversity, the purpose of the study was primarilyto determine any potential efficacy and hencepatients were considered nonresponders anddropped from the study if no regrowth was seenby 3 months (5).

Statistical analysis

For analysis of efficacy, the intention-to-treatpopulation, defined as all randomized patients,should be utilized.

Subject selection

Age

There is no age within the adult age range (18years old) that one would need to be particularlyconcerned about a differential effect on hairregrowth. However, those adults whose hair lossfirst began when they were less than 5 years of ageclearly may have a different response to therapy

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than those with a first episode of hair loss as anadult. This is also true for children whose firstepisode of hair loss occurred in infancy versus laterin childhood or adolescence. In addition, particu-lar attention should be paid to subjects with per-sistent alopecia totalis/universalis since infancy as

there is a potential for confusion with other inher-ited hair loss disorders with alopecia areata. Twoparticular disorders, atrichia with papular lesionsand vitamin D resistant rickets, have scalp hair atbirth that is shed over the first 23 years of life, and

with persistent total scalp alopecia thereafter (14).A scalp biopsy would differentiate these conditionsfrom alopecia areata.

Duration of current episode of hair loss

This is defined as from the time when hair growthwas last normal (excluding, if present, the hair loss

from the underlying conditions of male and femalepattern alopecia) to the present time. The followingsubgroups of hair loss duration are important toconsider in study design:1. 25 years5. >5 years

The duration of hair loss is primarily regardedas a marker of the potential for spontaneousregrowth, which is greatest during the first 2 years

after hair loss begins and much less likely after 5years of continued hair loss in a given area, particu-larly for those with alopecia totalis or universalis.However, duration of hair loss may also be linked toactivity of disease.

Activity of hair loss

Little is said of this factor in any clinical trial dis-cussion but it has important ramifications for theinitial response to therapy. Patients who are in avery active phase of loss at the beginning of a clini-cal trial most assuredly will have further hair lossbefore any regrowth can be stimulated by anyagent: this is because hairs have already moved outof anagen but have not yet been shed. If patients inan active shedding phase are included in a clinicaltrial, the subsequent immediate hair loss could bemisinterpreted as the therapy being ineffective.

Active loss is easily discernable clinically by a hairpull at the periphery of any loss and throughoutthe scalp: if active, the hairs will readily come outon gentle traction. In addition, active loss, and cor-roboration of alopecia areata, can be obtained by

looking for exclamation point hairs: the presenceof a few exclamation point hairs only confirms thepresence of alopecia areata but the presence ofmany is suggestive of a very active phase of loss.Finally, a biopsy of the scalp may be discriminatoryof the active phase versus quiescent, persistent

phase of hair loss with the lymphocytic swarm ofbees around the follicular bulb more commonwith active loss: how presence or absence of thelatter effects response to therapy has not beendetermined.

Pattern of hair loss

There are certain patterns of hair loss in alopeciaareata that have a poor prognosis. Alopecia totalis(AT:100%terminalhairlossonthescalp)andalope-cia universalis (AU: 100% terminal hair loss on thescalp and body) are clearly less treatment respon-

sive than patchy alopecia areata. An ophiasispattern of hair loss (hair loss around the peripheryof the scalp, largely sparing the central scalp) is alsomuch more treatment resistant. Any trial includingthese patterns of hair loss should have stratificationby pattern and the expectation that the response totreatment in these clinical subtypes will be muchless than in patchy alopecia areata.

Amount of hair loss

Many of the studies in the literature have includedboth patients with limited (50%) hair loss, most without stratification byamount of hair loss at baseline when reportingresults. Since the likelihood of spontaneousregrowth is inversely proportional to the amount ofloss and since the methods to track efficacy aredifferent when the hair loss is minimal versusextensive, the amount of hair loss is an appropriatevariable to use to stratify the patient population inclinical studies. The data on response to treatmentcorrelated with amount of hair loss at baselineshould be part of the results section of any clinicaltrial of alopecia areata.

Presence of body hair loss and/ornail involvement

These should be noted as potentially their pres-ence could imply a more generalized immuneresponse and affect the response to treatment ofscalp hair loss.

Concomitant conditions

Although there is an increased frequency of otherautoimmune disorders in patients with alopecia

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areata compared to the general population, mostpatients are free of other such conditions. However,occasionally patients may have multiple autoim-mune conditions and these patients may respondvery differently to treatment for their hair loss thanthose who have alopecia areata alone. Patients with

atopy (atopic dermatitis, allergic rhinitis, hay fever)may also have a less vigorous response to treat-ment than those without a history of atopy.

Although family history of alopecia areata maybe a negative prognostic factor, the difficulty in cor-roborating the history makes it difficult to use asa point of stratification of treatment groups in aclinical trial.

Efficacy assessment

Endpoints

Quantitative assessment of regrowth. The quanti-tative measures used to report regrowth prior to1990 were fairly crude or nonexistent. Patientsresponse to therapy were reported in qualitativeterms such as patchy or diffuse (15), someresponse, good response or good growth (16),significant regrowth (17) or full regrowth,almost full regrowth and improvement (11),often without attention to the amount of hair lossat baseline. Vellus as well as terminal hair was oftenrecorded in responders (16). One parameter used

to commonly assess efficacy has been cosmeti-cally acceptable hair growth (1719). Cosmeti-cally acceptable has been defined as amount ofterminal hair growth sufficient to cover the scalpand conceal areas of residual loss (19) or patientno longer needing a wig or cap to conceal hair loss(18,20). Most reports of cosmetically acceptableregrowth did not take into account the locationand/or amount of the hair loss at baseline, impor-tant variables effecting results. Hair loss on the topof the scalp is much less likely to end up as cos-metically acceptable compared to hair loss on thesides and back of the scalp unless the regrowth isnearly complete. The use or nonuse of a hairpieceby the patient adds another subjective aspect to theresponse.

Both Fiedler-Weiss and Price independently in1987 quantified the amount of hair loss at base-line, Fiedler-Weiss dividing hair loss into 024%,2574%, and 75100% subgroups and Price divid-ing the baseline hair loss into 2550%, 5175%,7699%, and 100% hair loss (18,19). Gupta et al.also added a scoring system for hair loss at base-line and at follow-up (0 = no loss, 1 = almost

totally free of hair loss, 2 = mild, 3 = mild to mod-erate, 4 = moderate, 5 = moderate to severe, and6 = severe hair loss, further defined as AU, AT, or>5 patches each >4 cm in diameter) and thenattached a quantitative measure to the term cos-metically acceptable regrowth (terminal hair

regrowth on more than 90% of the scalp) (21).Although this latter groups system allowed forexamination of the difference in response in those

with varying degrees of hair loss at baseline, thescoring system was still very subjective in nature,making comparison of results obtained by differ-ent investigators/sites difficult.

In 1992, Olsen et al. reported on the use of aquantitative assessment measure of hair loss in aprospective clinical trial to determine the potentialsynergistic effect of topical minoxidil with oral ste-roids in the treatment of alopecia areata (10). Olsenand her colleagues stratified the patient population

into the subcategories of baseline hair loss, i.e.,024%, 2549%, 5074%, 7599%, and 100%. Indetermining regrowth, the % of scalp hair loss wasdetermined and the % change in hair loss frombaseline determined at each follow-up visit. This

was then similarly put into categories of regrowth,i.e.,


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scalp surface area covered, was provided by Olsen

and Canfield. This aid facilitated a more accuratedetermination of hair loss and uniformity betweeninvestigators assessments. The subcategories of% scalp hair loss were given an official shorthanddesignation to facilitate communication amongcenters, mirroring the Olsen method of 1992.

S0 = no hair lossS1 25% hair lossS2 = 2549% hair lossS3 = 5074% hair lossS4 = 7599% hair loss

a = 7595%b = 9699%

S5 = 100% hair lossBody hair was rated for the first time as none,

some, or 100% (B0, B1, a n d B2, respectively) and nailinvolvement as none or some (N0 and N1) with asubcategory of N1 for 20 nail dystrophy (N1a).In this

way, the complete picture of a patients alopeciaareata at baseline could be described and classified(Example, S4aB1N0 for a patient with 80% scalp hairloss, eyelash loss but no other body hair loss andno nail involvement). The publication also gavea listing of potential information to gather in

the planned NAAF alopecia areata database, i.e.,demographic information, details of the history ofalopecia areata, family history of alopecia areata,and medical history of the patient and family.

In Part II, of the investigative guidelines, theSALT score was introduced (24). This formalized a

mathematical approach to the determination ofhair loss and hair regrowth. Briefly, the % of scalphair loss in each of the sides, back and top of thescalp were determined independently, each wasmultiplied by the % scalp covered in that area of thescalp and the products of each section summed fora final total % hair loss, designated as the Severity

Alopecia Tool or SALT score (FIG. 3a,b). This com-putation would be repeated at each visit during astudy and the change from baseline SALT score

would be the % regrowth. For example, if a patienthad 60% scalp loss at baseline and 35% scalp hairloss at follow-up by SALT score determination, this

is then a 42% change (regrowth) from baseline oran absolute 25% regrowth. The SALT score wasused for the first time in a commercially sponsoredclinical trial of alopecia areata in 20032005 (8).

Hair growth index. Bernardo et al. developed ascoring system for regrowth in alopecia areata thatincluded not only % of scalp hair regrowth but alsothe type of hairs regrowing in the areas of hair loss(8). Unlike other methods of assessing results, thismethod included an assessment of nonterminalhair growth. The percentage of scalp covered by

vellus, indeterminate or terminal hair was multi-plied by a weighting factor of 1 for vellus, 2 forindeterminate, and 3 for terminal. The sum ofthese products (0300) was the Hair Growth Indexscore and could be compared at each visit.

Although this scoring system was used in this pub-lication in a half-head study, it could be extendedto use in a parallel group treatment study. Theprimary utility of the Hair Growth Index wouldseem to be in the determination of whether a newagent induces any particular type of hair growthrather than in the determination of overall efficacy.

Response criteria

What is considered a significant response may varyby type of alopecia areata, amount of hair loss, andduration of hair loss and whether the purpose ofthe study is to show any efficacy of a new agentbefore moving forward with further trials. Olsenet al. in the active control study of systemic steroids

with or without topical minoxidil defined an objec-tive response as at least 25% terminal regrowthcompared to baseline (10). However, in her study,

FIG. 2. Olsen/Canfieldtool for determination of % scalphairloss. Percentages represent scalp surface area (reprinted with

permission).

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80% X 0.18 =14.48%

(a)

(b)

95% X 0.18 = 17.1%

65% X 0.40 = 26% 85% X 0.24 = 20.4%

SALT score

14.5% + 17.1% + 26% + 20.4% = 78%

95% x 0.18 = 17.1% 95% x 0.18 = 17.1%

50% x 0.40 = 20.0% 65% x 0.24 = 15.6%

SALT score

17.1% + 17.1% + 20% + 15.6% = 69.8%

FIG. 3. (a, b) Determination of SALT score in two patients with extensive scalp hair loss. For determination of efficacy,the SALTscore would be determined at baseline (BL) and each follow-up (F/U) visit and the percentage change from baseline determined

by the following:SALT BL SALT F/U

SALT BL100% %

- = change from baseline.


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of topical steroids alone, she focused on responsesof50% terminal hair regrowth in those with >50%loss at baseline (22). Wiseman et al., in their studyof patients who had topical DPCP applied by theinvestigator, defined significant regrowth as 75%of the scalp covered by terminal hair (3). Delemere

et al. in conducting an evidence-based review oftherapeutic options in alopecia areata definedclinically significant hair growth as >50% regrowthof the affected area (13). Talpur and Duvic usedterminology more common with cancer studies intheir study of topical bexarotene, i.e., a PhysicianGlobal Assessment of 50% improvement wasdefined as a partial response and 100% clearingdefined as a complete response (7).

As with psoriasis, an arbitrary % improvementcan be established as a benchmark for alopeciaareata. The NAAF subgroup on investigative guide-lines has suggested that this could be expressed by

a subscript number attached to the SALT (exampleSALT50, SALT75).This would be useful for comparingresults in various clinical trials, i.e., how manypatients were able to achieve a SALT50. However,going forward, it must be made very clear that thesubscript of 50 or 75 refers to a % change in hairloss from baseline and not to an absolute change in% hair loss from baseline.

Photographs

Standardized global photographs of the four views

of the scalp (top, both sides, and back) are stronglyencouraged to both help to corroborate the SALTscore determination at the bedside as well as totrack specific areas of hair loss. The photographscan be further utilized to do a global panel review atthe end of the study in which blinded experts ratethe hair growth response. Taking time to comb thehair for the photographs is very important so thatthe location and relative size of the areas of hair losscan be tracked at subsequent visits and also toenable direct comparison of the sequential photo-graphs of the hair loss during global panel review

Biopsy

A biopsy is not generally needed for the diagnosisof alopecia areata except in cases of diffuse alope-cia. However, the presence of active alopecia areata

with a peribulbar lymphocytic infiltrate aroundterminal follicles versus alopecia in the chronicphase where the hairs are miniaturized and theinfiltrate is less obvious (25) may impact on studyresults. In general, accounting for the duration ofcurrent episode of hair loss likely covers for this

difference in histology. Clinical trials have notroutinely included biopsies but they may offeradditional insight into variation of response, par-ticularly if biologic markers of disease activity areestablished.

Patient assessment

Several possible methods exist for capturingpatient assessment of response.a. Descriptive Assessment. Fiedler-Weiss had

patients use the same definition of cosmeti-cally acceptable hair growth as the investigatorin rating efficacy of topical minoxidil, i.e., nolonger needing cap or wig to conceal hair loss(18). Patients in the study by Wiseman et al.

were also asked to determine cosmeticallyacceptable regrowth but the definition was leftopen ended (3).

b. SALT Score. Patients can also be asked to usethe SALT score to determine their amount ofhair loss during a clinical trial but this methodrequires standardized photographs from thecurrent visit be either printed out or displayedelectronically for patients. This method isunlikely to be particularly useful if photographsare unable to capture the full extent of the hairloss. Before using this technique in an actualclinical trial, patients should be given adequateinstruction and experience with this tool.

c. Visual analog scale (VAS). A VAS is quantifiable

and easy for the patient to understand and use.In the efalizumab trial using a 100 mm VAS,patients were more likely to rate the hair loss inthe placebo group as negative than investiga-tors but both were in general accord with theresults (8).

d. Quality of life (QoL) questionnaire. A standard-ized QoL questionnaire specifically for alopeciaareata does not exist. However, validated QoLquestionnaires for skin disorders are availableand selected relevant questions could be uti-lized from them. For example, the first 17 ques-

tions of the Dermatology Quality of Life Scaleswas utilized in the efalizumab study (8). Analopecia areata-specific QoL questionnaire is agoal for Phase IIIII clinical trials.

Conclusions

After decades of case-control series assessing theefficacy of agents used to treat alopecia areata, weare now poised to conduct controlled clinical trialsof new agents. Given the recent leaps in under-

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standing of the etiological factor in alopecia areatagained from the NAAF national patient registry andthe subsequent genetic work done by Dr Christianoand colleagues, there is now the hope of identifyingnew effective treatments for alopecia areata. Wealso now have standardized methods to readily

assess the efficacy of these agents on the pathwaytoward the first FDA approval of a medication forthis condition.

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