54 Practical Dermatology July 2005

Alopecia Areata: Treatments, Alternative Options,

and Cosmetic Interventions

AAl o p e c i aareata is ad i s e a s ewith bothm e d i c a l

and cosmetic implica-tions, similar to acne,rosacea, psoriasis, and numerous other dermatoses. As derma-tologists, we recognize alopecia areata (AA) as a medical diseaseand subsequently treat it with medical means, yet we alsoacknowledge and address its cosmetic effects.

While our cosmetic approach to managing AA includes theuse of scalp colorants, scarves, turbans, hairpieces, and customprostheses, our medical approach relies on a growing armamen-tarium of increasingly sophisticated treatment options, withsulfasalazine, imiquimod, and the biologics representing someof the newest agents under evaluation. Below I’ll review old andnew treatment options and then outline a practical approach tomanaging patients with patchy, focal disease and patients withextensive disease.

A Growing ListDespite the availability of numerous treatments, no one agentstands out as superior. Efficacy varies from patient to patient,and it is sometimes difficult to differentiate treatment successfrom spontaneous remission, particularly in patients withpatchy, focal disease. Rather than actually altering the diseasecourse, we believe the immunomodulating agents, topical sen-sitizers, irritants, and other commonly used AA treatmentsstimulate hair growth by altering the peripheral immune sys-tem responsible for AA.1 To date, most studies have simplyassessed treatment efficacy on the basis of regrowth, but currentand future studies look more closely at a drug’s effect on hairfollicle differentiation and the inflammatory perifollicular-peribulbar infiltrate.

Steroids. Topical, intralesional, and oral steroids have a longhistory of use in AA, each with varying degrees of success. Onepossible hypothesis for the variable responses we see with glu-cocorticoid steroid thera-py may be related to ele-vated type II glucocorti-

coid receptors anddecreased levels of thiore-doxin, signifying inhibi-tion of cellular transcrip-tion, in some AApatients.

Topical steroids arecommonly used to treat patchy AA and less frequently forextensive AA. However, we have not yet determined the mini-mum and maximum effective strengths or classes of topicalsteroids for AA. Specifically, 0.2% fluocinolone acetonidecream, 0.1% halcinonide cream, 0.05% betamethasone dipro-pionate cream, and 0.05% clobetasol propionate have eachdemonstrated varying degrees of success in patients, but evi-dence of regrowth typically requires at least three months ofuninterrupted treatment.3-6 A retrospective review suggests thateven patients with more than 50 percent hair loss may achievesignificant regrowth with a class I-IV topical steroid.7 In fact, arecent study suggests severe, refractory forms of AA mayrespond to 0.05% clobetasol propionate under occlusion.6 Inanother small study of four cases of congenital AA, 0.05% clo-betasol propionate stood out as most effective when comparedto 2% minoxidil, 0.1% hydrocortisone, 0.05% betamethasonevalerate, and 0.05% fluocinonide, resulting in full regrowth in50 percent of patients.8

Intralesional steroids—triamcinolone acetonide or triam-cinolone hexacetonide—are also a commonly used treatmentoption for patients with less than 50 percent scalp involve-ment. Patients with rapidly progressive AA, extensive AA,and AA present for two or more years may respond morepoorly to this treatment.9 We typically use 5-10mg/mL of tri-amcinolone acetonide for scalp lesions and 5-10mg/mL forthe eyebrow area; on average, patients begin to experienceregrowth within two to six weeks of treatment. It’s importantto always inject the steroid just below the epidermis, forinjections deeper into fat may lead to atrophy and a poorresponse. Children and adolescents may require a topicalanesthetic, which we have our younger patients apply with

occlusion one hour priorto undergoing intrale-sional injections. By Maria K. Hordinsky, MD Minneapolis

The treatment armamentarium for alopecia areata continues to grow.

An expert outlines practical approaches to manage localized, patchy or

extensive disease.

July 2005 Practical Dermatology 55

Systemic steroids represent another treatment option, par-ticularly for patients with active disease and possibly for thosewith extensive disease. Although various dosing regimens havebeen used with success, one study suggests that the criticalthreshold to stimulate hair growth with systemic steroids in anadult is less than 0.8mg/kg daily.10 Specifically, the study foundthat a six-week tapering dose of oral prednisone beginning at40mg/day (tapering by 5mg/day weekly over four weeks andthen by 5mg/day every three days) resulted in 15 of 32 patientsachieving at least 25 percent regrowth; eight of the 15 patientsachieved more than 75 percent regrowth.10 Following the oralprednisone treatment with 2% topical minoxidil three timesper day for an additional 14 weeks may limit poststeroid hairloss.10 Studies have also shown an oral monthly pulse of 300mgprednisolone for a minimum of four doses may result in com-plete or cosmetically acceptable regrowth in some patients withwidespread disease.11 Alternatively, studies alsosuggest intravenous methylprednisolone maybenefit some patients with extensive multifo-cal AA or severe AA of recent onset but doesnot appear to offer significant benefit topatients with aphaisic AA, alopecia totalis, oralopecia universalis.12-14 Children with exten-sive, recent-onset AA have also been reportedto benefit from intravenous methylpred-nisolone (5mg/kg twice a day).15

Side effects deserve attention when consider-ing systemic steroids. These include diabetes,weight gain, hypertension, psychologicalchanges, osteoporosis, suppression of theadrenocorticotropic axis, striae, acne, hypertri-chosis, and purpura. To counter increased osteo-porosis risk, many clinicians prescribe calcium,vitamin D, or even Fosamax (alendronate sodi-um, Merck) to patients undergoing oral steroid therapy.

Minoxidil. The safety profile of topical minoxidil makesthis drug appealing to both patients and dermatologists, andstudies indicate that a twice daily application of 1-5% topicalminoxidil solution is capable of stimulating cosmeticallyacceptable hair regrowth, particularly in patients with less than75 percent baseline hair loss.16-18 Patients with patchy AA mayalso achieve cosmetically acceptable regrowth with 2% topicalminoxidil.17 Although regrowth may be seen as early as two tothree months into treatment, cosmetically acceptable regrowthmay take up to one year of treatment.17

One study suggests that patients with severe, treatment-resistant AA may achieve cosmetically acceptable regrowth with5mg of oral minoxidil administered every twelve hours, with amean time of 34.8 weeks to cosmetic response.19 However, it iscritical that patients taking oral minoxidil adhere to a 2g sodi-

um diet to limit fluid retention. Other side effects includeheadache; depression; lethargy; palpitations or tachycardia fol-lowing ingestion of caffeine, alcohol, or decongestants; andfacial hypertrichosis.

Topical Sensitizers. Although topical sensitizers dini-trochlorobenzene and squaric acid dibutylester have beenused in AA, diphencyprone represents the most commonlyused topical sensitizer for patients, including children, withsevere AA. Patients are normally sensitized to a two percentsolution, which typically requires two weeks. Weekly appli-cations ranging from 1.0, 0.5, 0.1, 0.05, 0.01, or 0.001 to0.0001 then follows. The concentration may vary through-out treatment, but the goal is to use a concentration capableof producing a mild allergic contact dermatitis (i.e. mild der-matitis without blistering or oozing). Cosmetically accept-able hair regrowth may require at least two years of therapy,

and patients may experience a three-monthlag between treatment initiation and signifi-cant hair regrowth.20 Response to diphen-cyprone appears to correlate with baselineextent of AA, age at disease onset, duration ofdisease prior to therapy, and presence of nailchanges.20,21 Furthermore, one study notedthat if AA becomes active, diphencypronedoes not reverse the process; and any newlyregrown hair is lost and sensitivity to diphen-cyprone may diminish.22

Anthralin. Topical anthralin representsanother treatment option for patients with stablealopecia areata. The concentration must be suffi-cient to elicit mild irritation and may range from0.2% to 1.0%. Although some patients mayachieve cosmetically acceptable regrowth with anovernight treatment of 0.5% anthralin cream,

one regimen suggests increasing the concentration to 0.75% if noregrowth is observed at six months.23 If patients still do notdemonstrate regrowth after six months with the 0.75% concen-tration, consider increasing to 1% anthralin, beginning with a 30-minute exposure time and then increasing to tolerance.

Light Therapy. Psoralen-ultraviolet A light (PUVA) hasresulted in complete hair regrowth for some patients withpatchy AA as well as patients with extensive disease. Oralpsoralens appear to be superior in efficacy to topical pso-ralens, which may be due to a systemic alteration in immunefunction.24,25 Although complete hair regrowth has beenachieved with 50 to 80 treatment sessions (three sessions perweek),25 hair loss is reportedly common following discontin-uation of therapy.26,27 Furthermore, concern regarding anincreased risk of malignant melanoma with more than 250treatments in psoriasis patients limits PUVA’s role in AA.28

Alopecia Areata

56 Practical Dermatology July 2005

Keep in mind

that

if the mean

follicular count

in horizontal

sections is

less than

1 follicle/mm2,

the prognosis

for regrowth

is poor.

UVB light therapy has also resulted in complete hair andbeard regrowth, although hair loss following discontinuation oftreatment may occur.29 In contrast, a recent study evaluating therole of photodynamic therapy in AA found no significant hairregrowth after 20 twice-weekly treatment sessions.30

Additional Options. Additional agents to consider forpatients with extensive AA include oral cyclosporine, isopri-nosine, thymopentin, nitrogen mustard, azathioprine, as wellas several combination regimens (see above). Recently, atten-tion has turned to newer agents such as sulfasalazine,imiquimod (Aldara, 3M), tacrolimus (Protopic, Fujisawa),and the biologics. A recent case report noting cosmeticallyacceptable regrowth in patients treated with sulfasalazine cou-pled with sulfasalazine’s excellent safety profile makes thisagent a reasonable option to try for patients with extensivedisease.31 Imiquimod may also play a role in the treatment ofalopecia areata. In a recent six-month trial, scalp biopsiesshowed increased anagen-telogen and terminal-vellus ratios.32

More recently, a case report noted regrowth following 11 to12 treatments with the 308nm xenon chloride excimer laser,with no relapse observed at five and 18 month follow-ups.33 Amulti-center clinical trial is currently evaluating the role ofAmiveve (alefacept, Biogen-Idec) in AA, and another multi-center clinical trial evaluating the role of Raptiva (efalizumab,Genentech) has been recently completed.

In contrast, a recent study found a twice-daily application of0.1% tacrolimus ointment for 24 weeks did not benefit patients,which may reflect insufficient depth of penetration of the oint-ment formulation.34 More recently, an open-label study with etan-ercept found this TNF-alpha inhibitor ineffective for patients

with moderate to severe AA, alopecia totalis, and alopecia univer-salis.35 None of the 17 patients demonstrated significant regrowthfollowing eight to 24 weeks of continuous treatment with 50mgof etanercept.

Managing the Patientwith Patchy, Focal AAWith the evidence for various treatments thus addressed, discus-sion moves to management of patients in the clinic. The majori-ty of AA patients have localized, patchy disease, and we recognizethat positive pull tests on the periphery of a patch as well as peach-colored patches indicate the disease is active. Many of our patientsalso exhibit a scalp dermatitis or report burning, pruritus, or tin-gling. Spontaneous remission is common in these patients, but asmall percentage of patients may experience progression of thedisease into a more extensive and chronic form of AA.36

When faced with a patient who has patchy, focal AA, in addi-tion to cosmetic cover-up, we commonly rely on topical orintralesional corticosteroids, topical minoxidil solution, andanthralin. In addition, since AA can occur anywhere on the scalp,we also commonly prescribe shampoo therapy, such as Clobex(clobetasol propionate 0.05%, Galderma) or Capex (fluocinoloneacetonide 0.01%, Galderma). Clobex is the agent we use mostfrequently with AA patients, and although more expensive thanother available agents, our patients tend to favor Clobex, findingit easy to apply, unlike many other topical steroid formulations.We instruct patients to apply Clobex to a dry scalp for 15 min-utes before rinsing it off in the shower. Double-blind, controlledstudies examining the efficacy of this approach in preventing aswell as treating patchy alopecia areata remain to be done.

July 2005 Practical Dermatology 59

Combination: Topical Minoxidil & Oral Prednisone10

Treatment Regimen: Six-week tapering dose of oral prednisone(starting at 40mg/day), followed by 2% topical minoxidil appliedeach day for up to 14 weeks.

Results: Topical minoxidil limited poststeroid hair loss in AApatients.

Combination: Topical Minoxidil & Betamethasone Dipropionate38

Treatment Regimen: Twice-daily application of 5% topical minoxi-dil, followed 30 minutes later by 0.05% betamethasone dipropi-onate cream.

Results: Fifty-six percent of patients with severe, chronically treat-ment-resistant AA achieved fair to good regrowth after 16 weeksof therapy.

Combination: Topical Minoxidil & Anthralin39

Treatment Regimen: Twice-daily application of 1mL 5% topicalminoxidil, an overnight application of anthralin appliedtwo hours following evening application of minoxidil.

Results: Terminal hair regrowth occurred in 39 of 50patients with severe, treatment-resistant AA by week 12. By week 24, 5 of 24 patients achieved cosmeticallyacceptable regrowth.

Reported Combination Regimens for the AA Patient

Alopecia Areata

Managing the Patient with Extensive AAFor the most part, dermatologists are quite comfortable manag-ing the patient with patchy AA. Our challenges tend to arisewhen patients present with extensive AA. When faced with thesepatients, treatment is based on histopathology. A recent studyenhanced our understanding of the histopathologic features ofAA, proposing that AA progresses through acute, subactue, andchronic stages.37 In the acute stage, we can expect to find theinflammatory infiltrate around the terminal hair bulb, while inthe subacute stage we begin to find decreased anagen hairs andincreased catagen and telogen hairs. In the chronic stage,decreased terminal hairs and increased miniaturized hairs arefound; rather than the normal 7:1 terminal-vellus ratio, thecommonly seen ratio is 1:1. However, patients who experiencerecurrent episodes demonstrate a mixture of these findings, andthe chronic cycling from anagen to telogen hairs prevents fullanagen follicle differentiation.

Therefore, based on examination of a patient’s biopsy, wecurrently select agents that target the histological findings:inflammation, follicular plugging, etc. We commonly select thebiopsy site approximately two inches above the ear on eitherthe left or right parietal scalp and do two four-millimeterpunch biopsies. One specimen is sectioned vertically and theother horizontally. In current and future studies, we are per-forming biopsies on patients who achieve hair regrowth or atthe end of the treatment phase to better understand a specifictreatment’s histopathologic effect. If the mean follicular countin horizontal sections is less than 1 follicle/mm2, the prognosisfor regrowth is reportedly poor.

A Promising FutureWithout doubt, we are moving forward in our understandingand management of AA. Optimism and interest continue to sur-round the potential role of the biologic agents, and we look for-ward to seeing the results of the current alefacept and efalizum-ab studies. In addition, the Alopecia Areata Registry will onlyfurther enhance our understanding of the genetic basis of AA, aswell as provide additional insight on the epidemiology of the dis-ease and quality-of-life issues associated with alopecia areata.

1.Alexis AF, Dudda-Subramanya R, Sinha AA. Alopecia areata: autoimmune basis of hairloss.Eur J Dermatol. 2004 Nov-Dec;14(6):364-70.2.Sawaya ME, Hordinsky MK. Why steroids may not always work in alopecia areata:elevated unoccupied glucocorticoid receptors and decreased levels of thioredoxin.Dermatol Therapy 2001 Dec;14(4):317-23.3.Pascher F, Kurtin S, Andrade R. Assay of 0.2 percent fluocinolone acetonide cream foralopecia areata and totalis. Efficacy and side effects including histologic study of the ensu-ing localized acneform response. Dermatologica. 1970;141(3):193-202.4. Montes LF. Topical halcinonide in alopecia areata and in alopecia totalis. J CutanPathol. 1977;4(2):47-50.5.Fiedler VC. Alopecia areata. A review of therapy, efficacy, safety, and mechanism.Arch Dermatol. 1992 Nov;128(11):1519-29.6.Tosti A, Piraccini BM, Pazzaglia M, Vincenzi C. Clobetasol propionate 0.05% underocclusion in the treatment of alopecia totalis/universalis. J Am Acad Dermatol. 2003July;49(1):96-8.

7.Oslen E. Topical and systemic corticosteroids in alopecia areata. Aust Dermatol1997;38:20 (abstract).8.Lenane P, Pope E, Krafchik B. Congenital alopecia areata. J Am Acad Dermatol. 2005Feb;52(2 Suppl 1):8-11.9. Abell E, Munro DD. Intralesional treatment of alopecia areata with triamcinolone ace-tonide by jet injector. Br J Dermatol. 1973 Jan;88(1):55-9.10. Olsen EA, Carson SC, Turney EA. Systemic steroids with or without 2% topical minox-idil in the treatment of alopecia areata. Arch Dermatol. 1992 Nov;128(11):1467-73.11. Sharma VK. Pulsed administration of corticosteroids in the treatment of alopecia area-ta. Int J Dermatol. 1996 Feb;35(2):133-6. 12.Perriard-Wolfensberger J et al. Pulse of methylprednisolone in alopecia areata.Dermatology. 1993;187(4):282-5.13.Friedli A et al. Pulse methylprednisolone therapy for severe alopecia areata: an openprospective study of 45 patients. J Am Acad Dermatol. 1998 Oct;39(4 Pt 1):597-602.14.Seiter S, Ugurel S, Tilgen W, Reinhold U. High-dose pulse corticosteroid therapy inthe treatment of severe alopecia areata. Dermatology. 2001;202(3):230-4.15.Kiesch N et al. Pulse steroid therapy for children’s severe alopecia areata.Dermatology. 1997;194(4):395-7.16.Fiedler-Weiss VC, West DP, Buys CM, Rumsfield JA. Topical minoxidil dose-responseeffect in alopecia areata. Arch Dermatol. 1986 Feb;122(2):180-2.17.Fiedler-Weiss VC. Topical minoxidil solution (1% and 5%) in the treatment of alopeciaareata. J Am Acad Dermatol. 1987 Mar;16(3 Pt 2):745-8.18.Price V et al. Topical minoxidil in the treatment of alopecia areata (Poster). SecondMeeting of the International Hair Research Societies, Washington, DC, 1998.19.Fiedler-Weiss VC et al. Evaluation of oral minoxidil in the treatment of alopecia area-ta. Arch Dermatol. 1987 Nov;123(11):1488-90.20.Wiseman MC, Shapiro J, MacDonald N, Lui H. Predictive model for immunotherapyof alopecia areata with diphencyprone. Arch Dermatol. 2001 Aug;137(8):1063-8.21.van der Steen PH et al. Prognostic factors in the treatment of alopecia areata withdiphenylcyclopropenone. J Am Acad Dermatol. 1991 Feb;24(2 Pt 1):227-30.22.Hull SM, Pepall L, Cunliffe WJ. Alopecia areata in children: response to treatment withdiphencyprone. Br J Dermatol. 1999 Aug;125(2):164-8.23.Fiedler-Weiss VC, Buys CM. Evaluation of anthralin in the treatment of alopecia area-ta. Arch Dermatol. 1987 Nov;123(11):1491-3.24.Weissmann I et al. PUVA-therapy for alopecia areata. An investigative study. ArchDermatol Res. 1978 Aug 28;262(3):333-6.25.Claudy AL, Gagnaire D. PUVA treatment of alopecia areata. Arch Dermatol. 1983Dec;119(12):975-8.26.van der Schaar WW, Sillevis Smith JH. An evaluation of PUVA-therapy for alopeciaareata. Dermatologica 1984;168(5):250-2.27.Taylor CR, Hawk JL. PUVA treatment of alopecia areata partialis, totalis and univer-salis: audit of 10 years’ experience at St John’s Institute of Dermatology. Br J Dermatol.1995 Dec;133(6):914-8.28.Stern R, Nichols K, Vakeva L. Malignant melanoma in patients treated for psoriasiswith methoxsalen (psoralen) and ultraviolet A radiation (PUVA). N Engl J Med. 1997Apr;336(15):1041-45.29.Krook G. Treatment of alopecia areata with Kromayer’s ultra-violet lamp. Acta DermVenereol. 1961;41:178-81.30.Bissonnette R et al. Topical photodynamic therapy with 5-aminolaevulinic acid doesnot induce hair regrowth in patients with extensive alopecia areata. Br J Dermatol. 2000Nov;143(5):1032-5.31.Ellis CN, et al. Sulfasalazine for alopecia areata. JAAD. 2002 Apr;46(4):541-4.32.Steiner LP et al. Effect of Aldara 5% cream on anagen:telogen and terminal:vellusratios in extensive alopecia areata. Poster Presentation, Fourth International AlopeciaAreata Research Workshop, Washington DC, November, 2002.33.Gundogan C, Greve B, Raulin C. Treatment of alopecia areata with the 308-nmxenon chloride excimer laser: case report of two successful treatments with the excimerlaser. Lasers Surg Med. 2004:34(2):86-90.34.Price VH, Willey A, Chen BK. Topical tacrolimus in alopecia areata. J Am AcadDermatol. 2005 Jan;52(1):138-9.35.Strober BE et al. Etanercept does not effectively treat moderate to severe alopeciaareata: an open-label study. J Am Acad Dermatol. 2005 Jun;52(6):1082-4.36. Safavi KH et al. Incidence of alopecia areata in Olmsted County, Minnesota, 1975through 1989. Mayo Clin Proc. 1995 Jul;70(7):628-33.37.Whiting DA. Histopathologic features of AA: a new look. Arch Dermatol. 2003Dec;139(12):1555-59.38.Ferry JJ, Fiedler VC. Pilot study to evaluate the effect of topical betamethasone dipro-pionate on the percutaneous absorption of minoxidil from 5% topical solution. J InvestDermatol. 1990;94:524 (abstract).39.Fiedler VC et al. Treatment-resistant alopecia areata. Response to combination thera-py with minoxidil plus anthralin. Arch Dermatol. 1990 Jun;126(6):756-9.Portions based on a presentation from the AAD Annual Meeting, February 2005, NewOrleans, LA.

60 Practical Dermatology July 2005

Alopecia Areata