treatment of alopecia areata

UPDATE ON HAIR DISORDERS 0733-8635/96 $0.00 + .20

TREATMENT OF ALOPECIA AREATA

Virginia C. Fiedler, MD, and Samer Alaiti, MD

Alopecia areata is a common dermatologic problem accounting for approximately 2% of new outpatient dermatology clinic visits. The course of alopecia areata is extremely variable, with some cases showing spontaneous remission and others undergoing total scalp and body hair loss. Alopecia areata, especially when severe, often profoundly affects the lives of those afflicted. The unpredictability of its severity and frequency of recurrence may lead to feelings of loss of control and helplessness.

Severe forms of alopecia areata are extensive or rapidly progressive and are likely to be chronic or at least chronically recurrent and often resistent to treatment. There is no good evidence to suggest that drug-induced remissions occur or that therapy alters the ultimate course of the disease. At best, treatments suppress the underlying immunologic process when it is active. Long-term treatment may be necessary to elicit and maintain cosmetically adequate hair growth in patients with severe disease; therefore, both safety and efficacy are critical therapeutic concerns..

GLUCOCORTICOSTEROIDS

lntralesional Steroids

Intralesional steroids are a common form of treatment for alopecia areata. This method

is best used for stable patchy scalp hair loss. Patients with extensive alopecia areata, rapidly progressive disease, or hair loss greater than 2 years’ duration of the current episode generally respond poorly to intralesional steroids.*

Side effects of intralesional steroids include minimal transient atrophy and, rarely, follicu- lar atrophy.33 Local pain at the injection site is the most frequent patient complaint; it is a significant drawback in treating children.

Topical Steroids

Topical steroids have not been extensively evaluated, although they are frequently used to treat alopecia areata, especially in children. Our experience16 using 0.05% betamethesone dipropionate cream in the nonoptimized vehicle (DiprosoneB) parallels that reported by Pascher et a135 who used 0.2% fluocinolone acetonide cream (Synalar HPB). Twice daily applications of Diprosone cream without oc- clusion seem to work particularly well in children (even in some with 100% hair loss). This approach may also be beneficial in adults. Three months of uninterrupted treatment are necessary to evaluate for early hair regrowth. Treatment of the entire scalp seems to be most effective to elicit cosmetically adequate hair growth in individuals with widespread or actively flaring disease. Cosmetically ade-

From the Department of Dermatology, University of Illinois at Chicago, Chicago, Illinois

DERMATOLOGIC CLINICS

VOLUME 14 * NUMBER 4 OCTOBER 1996 733

734 FIEDLER & ALAITI

quate regrowth may take many months to achieve. Chronic treatment may be required to maintain cosmetically adequate hair growth. Hair loss may flare despite maintenance therapy, but usually appears to be minimized when compared with the severity of previous untreated episodes of loss.16

Side effects of topical steroid therapy as outlined consist most commonly of local folliculitis and occasionally acneiform facial le- sions; young children may develop reversible hypertrichosis on the face or neck. Daily shampooing and sparing applications (0.5 to 1 g applied to the entire scalp per application) seem to markedly diminish the occurrence and severity of these effects. Use of super high potency topical steroids is limited by telangiectasia formation and local atrophy. No systemic side effects have been reported with topical steroid treatment of alopecia areata, although careful monitoring of the growth curve in children as a marker for hy- pothalamic-pituitary-adrenal axis suppres- sion is advisable. In 15 years of using topical betamethasone dipropionate twice daily as outlined, the authors have seen no systemic side effects even in children as young as 2 years of age and older who are receiving long-term maintenance therapy.16

Systemic Steroids

Systemic steroids are most likely to be pre- scribed for rapidly progressive or extensive alopecia areata. It is argued by some that this form of therapy not only may stop active hair loss but also may beneficially affect the natural course of the disease. Our experience and that of other investigators indicate that active hair loss does not always- cease with systemic steroid therapy, hair loss may rapidly recur after cessation of treatment, and the disease may progress to alopecia totalis/ universalis despite systemic steroid ther-

Reported .side effects of systemic steroid therapy in alopecia areata are diabetes, striae, acne, hypertrichosis, purpura, pseudoacan- thosis nigricans, dysmenorrhea, weight gain, abdominal pain, hypertension, psychosis and other psychological difficulties, lenticular opaci- ties, cataracts, osteoporosis, and impaired ad- renocorticotropic hormone reserve.I6

The mechanism of steroid effect in alopecia areata is thought to be imrnunomodulatoryl6; however, direct effects of steroids on hair fol-

aPY.4, 37*45

licles may also be relevant to hair regrowth in alopecia a ~ e a t a . ~ ~

ANTHRALIN

Anthralin is the only irritant substance generally agreed to induce hair regrowth in alopecia areata.'O, 40 In our experience using anthralin (DrithocremeB) applied overnight to the entire scalp in concentrations of 0.5% or 1.0% used as a short (20- to 60-minute) application, the mean time to response was approximately 3 months. Cosmetic response took as long as 60 weeks to achieve and was seen in approximately 30% of patients with less than 75% scalp hair loss and in 20% of patients with 75% or greater (including 100%) scalp hair loss. Cosmetic response was maintained in approximately 75% of patients who continued treatment.1°

Our current therapeutic regimen for anthralin is to use the 1.0% cream (Dritho- creme@) in sparing applications for a short contact (20 to 60 minutes) time on alternate days for 2 weeks and then, if tolerated, continue with daily applications. Patients are in- structed to apply the medication to the entire scalp if the disease is widespread or actively flaring. They shampoo the medication off the scalp at the end of the appropriate time inter- val. They are cautioned to wash their hands thoroughly after applying anthralin and to avoid touching any fabric with their treated scalp until after they have shampooed.

Side effects of anthralin are pruritus, ery- thema, scaling, folliculitis, local pyoderma, and regional lymphadenopathy. These reactions are minimized with sparing applications and prompt shampooing. They resolve quickly if treatment is withheld for a few days and then reinstituted for shorter times. It is debated as to whether clinically evident inflammation is necessary to elicit a response. Early in the course of treatment, most patients experience at least minimal clinical evidence of inflammation that usually does not recur after some months of treatment despite apparent continued response to anthralin.

The mechanism of anthralin's effect in alopecia areata can only be speculated on.16 An- thralin has been shown to be toxic to Langer- hans cells,3O and it has been shown to be associated with a decrease in dermal T cells in treated psoriatic lesion^.^

TREATMENT OF ALOPECIA AREATA 735

MI NOXl DI L

Topical minoxidil may be effective in alopecia areata, especially when used in the 5% concentration. The lower concentration (2%, Rogaine) is most likely to be effective in mild patchy alopecia areata.@ One study of patients with severe chronically treatment-resistant disease who received twice daily applications of 5% minoxidil to the entire scalp showed cosmetic regrowth in 4 (37%) of 11 patients with 25% to 74% loss and in 2 (6%) of 36 patients with 75% to 100% loss.11 An- other study of patients with 25% to 99% hair loss reported cosmetic regrowth in 12 (48%) of 25 patients.38 The mean time to response is approximately 3 months and to maximum response is generally approximately 1 year. Cosmetic response is usually maintained with continued total scalp application of 5% minoxidil, although small patches may periodi- cally develop and then regrow during maintenance treatment.", 38

Side effects of topical minoxidil are usually minimal. Mild local irritation is seen occasionally, and rarely patients develop allergic contact dermatitis to minoxidil or to the pro- pylene glycol in the vehicle (VCF, unpub- lished observation). Rarely, photoallergic contact dermatitis has been reported.41 Systemic absorption of minoxidil is minimal even at the 5% concentration. No systemic side effects of topical minoxidil have been reported. Mild hypertrichosis, especially of the face, is some- times reported. In our experience, this is rarely associated with any evidence of in- creased percutaneous absorption; it is usually, but not always, related to local contami- nation of the skin from the patient's hands, the solution dripping onto the face and. not being washed off, or transfer of drug from a contaminated pillow case if the patient ap- plies the minoxidil less than 1 hour prior to bed time.I6

Oral minoxidil was evaluated in 65 patients with severe, chronically treatment-resistant alopecia areata.I2 This study was done in an effort to evaluate the maximal efficacy of minoxidil by circumventing the limitations of the topical preparation (ie, limited solubility and poor percutaneous absorption of minoxidil). Minoxidil was used as a single dose of 10 mg/d. Mean time to response was approximately 9 weeks and to cosmetic response was approximately 35 weeks. Hair regrowth progressed more rapidly and was more extensive with oral minoxidil than with topical

5% minoxidil. Cosmetic response was achieved in 12 of 65 (18%) chronically treatment-resistant patients with extensive disease. Cosmetic regrowth was maintained during treatment, although minor episodes of hair loss occurred in some patients.12

Side effects of oral minoxidil may be severe in hypertensive patients and include reflex tachycardia, edema, transient T-wave changes in electrocardiograms, and rare pericardial ef- fusion. In normotensive patients, low dose (10 mg/d) oral minoxidil was associated with periorbital edema and swelling of the fingers unless patients adhered strictly to a 2 g so- dium diet. Women occasionally complained of headaches, depression, or lethargy. Pa- tients occasionally complained of palpitations or tachycardia after ingestion of caffeine, alco- hol, or decongestants. Facial hypertrichosis occurred in 11 of 65 patients (17%). No elec- trocardiographic or echocardiographic abnor- malities were found.12

The mechanism of minoxidil effect in alopecia areata is not known; however, it seems likely that it may have direct stimulatory effects on the miniaturized follicles of alopecia areata.16 Whether or not minoxidil may also have a direct or indirect immunomodality effect in alopecia areata is currently an unre- solved issue.13, 25

PHOTOCHEMOTHERAPY

Psoralen plus ultraviolet A light (PUVA) has been evaluated as a treatment for alopecia areata in several studies.6, 24, 27, 31, 43 Treatments are given two to three times weekly. Time to response is reported as 20 to 40 sessions, with a maximum response being achieved within 1 year. Cosmetic response varies considerably, generally being more likely to occur in patients with patchy disease and in those receiving total body irradiation. Maintenance of cosmetic response varies, but it does not seem to be superior to that of other treatments. Inconvenience and cost are additional consid- erations in pursuing this course of therapy.

Side effects of PUVA treatment generally include nausea, pigmentary changes, risk of skin cancer formation, and cataracts; nausea was the only reported side effect in patients treated for alopecia areata.16

The mechanism whereby PUVA may facili- tate hair regrowth in alopecia areata may be immunomodulatory.16


CYCLOSPORIN A

Topical cyclosporin has been evaluated as a treatment for alopecia areata and generally has been found to be ineffective, probably because of its poor penetrati~n.~, 7, zo

Oral cyclosporin A has been reported to have some therapeutic efficacy in severe alopecia areata. Several case reports19, zz, 34 and one small studyZ3 have reported variable in- duction of hair growth. After discontinuation of treatment, hair loss recurred in patients who had shown hair regrowth. Side effects of oral cyclosporin A are potentially numerous and include nephrotoxicity, hypertension, hepatotoxicity, neurologic reactions, gastroin- testinal upset, and malignancies. The mechanism of cyclosporin effect is probably immunomodulatory, but it may also exert a direct effect on the hair follicle.16

OTHER SINGLE-AGENT TREATMENTS

Other agents reported to have some benefit in alopecia areata include ino~iplex,'~, 18, z8

thymopentin,3z, 42 nitrogen mustard; zinc? z9, 46 azathioprine,2l imipramine,36 and sul- fonesZ6

COMBINATION THERAPIES

Topical 5% minoxidil combined with topical steroid (0.05% betamethasone dipropionate cream applied 30 to 60 minutes later) has been evaluated in a double-blind trial and was found to be superior to either drug used alone when treating severe, treatment-resistant disease. After 16 weeks of treatment to the entire scalp, fair to good regrowth was found in 56% of patients on combination therapy, 13% on placebo, 22% on steroids alone, and 27% on minoxidil alone. Cosmetic response following combination therapy was seen in 16% of patients with 100% scalp hair loss, 16% with 75% to 99% loss, 48% with 25% to 74% loss, and 63% with 0% to 24% loss. No systemic and only mild local irritant side effects were seen.15 This apparent syner- gistic effect can be explained not only by the probable different mechanisms of action associated with each of the drugs, but possibly also by enhanced dermal residence time of min~xidil.~

Topical minoxidil and anthralin may be

successfully combined to treat alopecia areata.14 This combination was evaluated in 49 patients who had been previous treatment failures to anthralin, minoxidil, or both, used as single-agent treatments. Minoxidil 5% solution was applied twice daily; anthralin 0.5% cream (DrithocremeB) was applied at bed- time, 1 or more hours after the second minoxidil application. Both medications were applied to the entire scalp. Hair regrowth was seen in 38 of 49 patients (78%) at week 12; cosmetic response was achieved in 5 of 45 patients (11%) by week 24, at which point the study was terminated. Long-term cosmetic efficacy was not established; however, the five cosmetic responders continued treatment be- yond 6 months, and 4 of the 5 (80%) did maintain cosmetic efficacy with ongoing therapy for 84 weeks follow-up. Side effects were limited to irritant reactions that were mild in all but one patient who had to be discon- tinued from the study because of the dermatitis. No systemic minoxidil effects were noted despite some instances of enhanced systemic minoxidil ab~orption.'~

SUMMARY

Some individuals question whether any treatment is effective in severe alopecia areata. Certainly many patients, especially those with mild disease, experience spontaneous hair regrowth; however, results of double- blind studies clearly indicate that some treatments do promote hair regrowth even in those with extensive disease. Some patients never show either spontaneous or treatment- related hair regrowth; others experience hair regrowth only ,while maintained on treatment, repeatedly losing hair within a few weeks of discontinuing treatment and re- growing it within several weeks after restart- ing treatment. Some patients who have been responsive to treatment may experience exac- erbation of their disease such that even high- dose systemic steroids do not prevent the development of alopecia universalis. Some treatments appear to work on some patients some or all. of the time, but no treatment appears to work on all patients all of the time. We would suggest a few practical points that we find useful: To maximize the potential for cosmetic hair growth in alopecia areata that is extensive or flaring, treat the entire scalp instead of "chasing" patches. Do not change any topical treatment sooner than 3 months

TREATMENT OF ALOPECIA AREATA 737

after starting it; early regrowth may first be present at 3 months. Cosmetic regrowth may take a year or more to achieve. Maintenance treatment increases the likelihood of maintenance of cosmetic hair growth, but patches of hair loss may still come and go. Atopic patients who experience seasonal hair loss may benefit (ie, have less severe hair loss flares or respond more readily to topical therapy) by using an antihistamine or mast cell stabilizer prophylactically. Whether one looks at the therapeutic cup as half full or half empty, most patients urge us to continue to try to find safe, effective long-term treatments for this disease.

References

1. Abell E, Munro DD: Intralesional treatment of alopecia areata with triamcinolone acetonide by jet injection. Br J Dermatol 88:55-59, 1973

2. Arrazola JM, Sendagorta E, Harto A, Led0 A: Treat- ment of alopecia areata with topical nitrogen mustard. Int J Dermatol24608410,1985

3. Baker BS, Swain AF, Griffiths CEM, et al: The effects of topical treatment with steroids or dithranol on epidermal lymphocytes and dendritic cells in psoriasis. Scand J Immunol 22:471477, 1985

4. Burton JL, Shuster S: Large doses of glucocorticoid in the treatment of alopecia areata. Acta Derm Venereol 55:493496, 1975

5. Caulson IH, Holden C A Topical cyclosporin A in alopecia totalis: Failure of therapeutic effect due to lack of penetration. Br J Dermatol 121:53-54, 1989

6. Claudy AL, Gagnaire D: PUVA treatment of alopecia areata. Arch Dermatol 119:975-978, 1983

7. deProst Y, Teillac D, Paquez F, et al: Placebo-controlled trial of topical cyclosporin A in severe alopecia areata. Lancet 2803-804, 1986

8. Ead RD: Oral zinc sulphate in alopecia areata: A double-blind trial. Br J Dermatol 104:483484, 1981

9. Ferry JJ, Fiedler VC: Pilot study to evaluate the effect of topical betamethasone dipropionate on the percutaneous absorption of minoxidil from 5% topical so- 1ution:J Invest Dermatol 94:504, 1990

10. Fiedler-Weiss VC, Buys CM: Evaluation of anthralin in the treatment of alopecia areata. Arch Dermatol

11. F:edler-Weiss VC: Topical minoxidil . solution (1% and 5%) in the treatment of alopecia areata. J Am Acad Dermatol 16:745-748, 1987

12. Fiedler-Weiss VC, Rumsfield J, Buys CM, et a1 Evalu- ation of oral minoxidil in the treatment of alopecia areata. Arch Dermatol 123:1488-1490, 1987

13. Fiedler VC, Buys CM: Immunohistochemical charac- terization of the cellular infiltrate in severe alopecia areata before and after minoxidil treatment. Derma- tologica 175(Suppl 2):29-35, 1987

14. Fiedler VC, Wendrow A, Szpunar GJ, et al: Treat- ment-resistant alopecia areata response to combination therapy with minoxidil plus anthralin. Arch Der- matol 126:756-759, 1990

15. Fiedler VC: Alopecia areata: Current therapy. J Invest Dermatol 9669S708, 1991

123:1491-1493, 1987

16. Fiedler VC: Alopecia areata. Arch Dermatol 1281519- 1529, 1992

17. Galbraith GMP, Thiers BH, Fudenberg HH: An open- label trial of immunomodulation therapy with inosiplex (Isoprinosine) in patients with alopecia totalis and cell-mediated immunodeficiency. J Am Acad Dermatol 11:224-230, 1984

18. Galbraith GMP, Thiers BH, Jensen JJ, Hoehler F: A randomized double-blind study of inosiplex (Isopri- nosine) therapy in patients with alopecia totalis. J Am Acad Dermatol 16:977-983, 1987

19. Gebhart W, Schmidt JB, Schemper M, et al: Cyclosporin-A-induced hair growth in human renal allograft recipients and alopecia areata. Arch Derma- to1 Res 278:238-240, 1986

20. Gilhar A, Pillar T, Etzioni A: Topical cyclosporin A in alopecia areata. Acta Derm Venereol69:252-253, 1989

21. Goddard CJR, August PJ, Whorwell PJ: Alopecia totalis in a patient with Crohn’s disease and its treatment with azathioprine. Postgrad Med J 65:188-189, 1989

22. Gupta AK, Ellis CN, Tellner DC, Voorhees JJ: Cyclosporine A in the treatment of severe alopecia areata. Transplant Proc 3:105-188, 1988

23. Gupta AK, Ellis CN, Cooper KD, et a1 Oral cyclosporine for the treatment of alopecia areata: A clinical and immunohistochemical analysis. J Am Acad Dermatol22:242-250, 1990

24. Healy E, Rogers S: PUVA treatment for alopecia areata-Does it work? A retrospective view of 102 cases. Br J Dermatol 129:4244, 1993

25. Khoury EL, Price VH, Abdel-Salam MM, et al: Topi- cal minoxidil in alopecia areata: No effect on the perifollicular lymphoid infiltration. J Invest Dermatol 99:4047, 1992

26. Knauber J, Zaun H: Pathogeneseorientierte Thera- pieversuche bei alopecia areata. Akt Dermatol

27. Lassus A, Kianto U, Johansson E, Juvakoski T: PUVA treatment for alopecia areata. Dermatologica 161:29& 304, 1980

28. Lowy M, Ledoux-Corbusier M, Achten G, Wybran J: Clinical and immunologic response to Isoprinosine in alopecia areata and alopecia universalis: Association with autoantibodies. J Am Acad Dermatol 12:78-84, 1985

29. Lutz G, Styzinski K, Kreysel HW: Interet du zinc dans le traitement de la pelade. Nouv Dermatol 10:652-653,1991

30. Morhenn VB, Orenberg EK, Kaplan J, et al: Inhibition of a Langerhans cell-mediated immune response by treatment modalities useful in psoriasis. J Invest Der- matol 81:23-27, 1983

31. Orecchia G, Douville H, Marelli MA: PUVA treatment in extensive alopecia areata. Ann Ital Derm Clin Sper 42:277-282, 1988

32. Orecchia G: Thymopentin in the treatment of alopecia areata. Dermatologica 178:231, 1989

33. Orentreich N, Sturm HM, Weidman AI, Pelzig A: Local injection of steroids and hair regrowth in alope- cias. Arch Dermatol 82894-902, 1960

34. Paquet P, Arrese Estrada J, Pierard GE: Oral cyclosporine and alopecia areata. Dermatology 185:314315, 1992

35. Pascher F, Kurtin S, Andrade R: Assay of 0.2% fluocinolone acetonide cream for alopecia areata and totalis. Dermatologica 141:193-202, 1978

36. Perini G, Zara M, Cipriani R, et al: Imipramine in alopecia areata: A double-blind, placebo-controlled study. Psychother Psychosom 61:195-198, 1994

16:348-352, 1990


37. Perriard-Wolfensberger J, Pasche-Koo F, Mainetti C, et al: Pulse of methylprednisolone in alopecia areata. Dermatology 187:282-285, 1973

38. Price VH: Topical minoxidil in extensive alopecia areata, including three-year follow-up. Dermatolog- ica 175(Suppl 2):36-41, 1987

39. Sawaya ME, Hordinsky MK: Glucocorticoid regula- tion of hair growth in alopecia areata. J Invest Der- matol 104:30S, 1995

40. Schmoeckel C, Weissman I, Plewig G, Braun-Falco 0 Treatment of alopecia areata by anthralin-induced dermatitis. Arch Dermatol 11531254-1255, 1979

41. Tosti A, Bardazzi F, DePadova MP, et al: Contact dermatitis to minoxidil. Contact Dermatitis 13:275- 276, 1985

42. Tosti A, Manuzzi P, Gasponi A: Thymopentin in the treatment of severe alopecia areata. Dermatologica 177:170-174, 1988

43. Van der Schaar WW, Smitt JHS: An evaluation of PUVA therapy for alopecia areata. Dermatologica

44. Weiss VC, West DP, Fu TS, et al: Alopecia areata treated with topical minoxidil. Arch Dermatol 120:457463, 1984

45. Winter RJ, Kern F, Blizzard RM: Prednisone therapy for alopecia areata: A follow-up report. Arch Derma-

46. Wolowa F Behandlung von Alopecia Areata Totalis und Maligna mit Solvezink. 2 Hautkr 57393405, 1982

168:250-252, 1984

to1 1121549-1552, 1976

Address reprint requests to Virginia C. Fiedler, MD

Department of Dermatology University of Illinois at Chicago

840 South Wood Street M/C 624 376 Clinical Sciences Building

Chicago, IL 60612

treatment of alopecia areata

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