- Email: [email protected]
Management of hair loss diseases
DERMATOLOGICA SINICA 28 (2010) 139–145
R EVI EW ARTIC LE
Management of hair loss diseases Manabu Ohyama* Department of Dermatology, Keio University School of Medicine, Tokyo, Japan
KEY WO R D S
AB S T R ACT
Alopecia areata Androgenetic alopecia Bulge stem cells Scarring alopecia Telogen effluvium Transverse section Trichoscopy
The treatment of hair loss diseases is sometimes difficult because of insufficient efficacy and limited options. However, recent advances in understanding of the pathophysiology and development of new remedies have improved the treatment of refractory hair loss conditions. In this article, an update on the management of hair loss diseases is provided, especially focusing on recently reported therapeutic approaches for alopecia areata (AA). An accurate diagnosis is indispensable to optimize treatment. Dry dermoscopy represents new diagnostic techniques, which could enable the differentiation of barely indistinguishable alopecias, e.g. AA and trichotillomania. An organized scalp biopsy adopting both vertical and transverse sectioning approaches also provides a deep insight into the pathophysiology of ongoing alopecias. Among various treatments for AA, intraregional corticosteroid and contact immunotherapy have been recognized as first-line therapies. However, some AA cases are refractory to both treatments. Recent studies have demonstrated the efficacy of pulse corticosteroid therapy or the combination of oral psoralen ultraviolet A therapy and systemic corticosteroids for severe AA. Previous clinical observations have suggested the potential role of antihistamines as supportive medications for AA. Experimental evaluation using AA model mice further supports their effectiveness in AA treatment. Finasteride opens up new possibilities for the treatment of androgenetic alopecia. For androgenetic alopecia patients refractory to finasteride, the combination of finasteride with topical minoxidil or the administration of dutasteride, another 5 alpha-reductase inhibitor, may provide better outcomes. Scarring alopecia is the most difficult form of hair loss disorder to treat. The bulge stem cell area is destroyed by unnecessary immune reactions with resultant permanent loss of hair follicle structures in scarring alopecia. Currently, treatment options for this hair loss disorder are extremely limited. The development of effective therapies for this form of intractable alopecia represents an important issue to be resolved. Copyright © 2010, Taiwanese Dermatological Association. Published by Elsevier Taiwan LLC. All rights reserved.
Introduction Hair loss diseases, represented by alopecia areata (AA) or androgenetic alopecia (AGA), are relatively common dermatological problems encountered in daily practice.1,2 Although effective therapies are readily available for some types of alopecia, treatment options for certain subsets are
*Corresponding author. Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan. E-mail: [email protected]
extremely limited with unfavorable outcomes Accordingly, attempts have been made to develop or improve therapeutic approaches for intractable alopecia. In this review, recent advances in the management of hair loss diseases, including new techniques that enable proper diagnosis, novel therapeutic approaches and future perspectives are summarized. Particular emphasis is placed on the treatments for severe AA. Although remarkable progress has been made in the molecular biological understanding of genetic hair loss or anomalies, these conditions are not discussed in this article because they are rare.
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M. Ohyama
Advances in diagnostic procedures A correct diagnosis is indispensable to select and perform optimal treatment for hair loss diseases. Hair loss conditions with distinct clinical manifestations, such as typical AA and AGA, can be easily diagnosed based on the pattern of hair loss or the shape of fallen out hair shafts. However, some hair loss conditions are not diagnosable just by routine clinical evaluations. Dermoscopy is a useful device, especially for the evaluation of pigmentary lesions, including melanoma.3 The use of videodermoscopy or dry dermoscopy (dermoscopy without an immersion gel) enhances the diagnostic capacity in some hair loss conditions.4–7 Inui et al6 reported that yellow dots and short vellus hairs are the most sensitive markers of AA, while hair diameter diversity is an essential feature of AGA. Scalp dermoscopy also provides a powerful tool to differentiate clinically resembling hair loss conditions. Trichotillomania in which habitual or unconscious hair pulling causes mostly discrete alopecic patches, sometimes presents with an AA-like appearance (Figure 1A). Such lesions can be easily distinguished from AA by dermoscopy. Characteristic dermoscopic findings of trichotillomania are black dots and broken hairs without tapering hairs or small vellus hairs (Figure 1B).6,7 Dermoscopy is useful for the diagnosis of hair loss conditions as well as the evaluation of disease activity. For example, the presence of such findings as tapering hairs and short vellus hairs is correlated with AA disease activity.6 Collectively, the use of dermoscopy for the diagnosis of hair loss disorders is highly recommended. Scalp biopsy may not be included in “routine” diagnostic procedures for hair loss conditions. However, histopathological investigation of alopecic lesions is sometimes necessary to make a final diagnosis (e.g. scarring alopecia) or better understand the pathophysiology of the ongoing disease. It has
A
been reported that transverse sections of punch scalp biopsy specimens enable quantitative morphometric analysis of hair follicles.8 Factors that are indispensable for pathological interpretation of hair loss conditions, including total hair follicle number, the telogen/anagen ratio, and the ratio between terminal and vellus hairs, cannot be determined by conventional vertical sections (Figure 2).9,10 In addition, by slicing a sample into 3–4 disks (so that each disk contains infundibulum, isthmus, suprabulbar and bulbar regions) and embedding the same side down into the same cassette, several levels of hair follicles can be investigated on a single slide (Figure 2).11 Ideally, transverse sections should be prepared from both affected and unaffected sites for comparison.10 Although transverse scalp sections exceed conventional vertical sections in many aspects, some key pathological information is barely detectable by the transverse sectioning approach.12 For example, changes in the dermo-epidermal junction (interface change) cannot be appropriately assessed by the transverse approach. Thus both transverse and vertical sections are valuable in the diagnosis of hair loss disorders.13 In our hair disease clinic, a standard histopathological investigation includes two 4 mm punch biopsy samples obtained from affected lesions (one for transverse sections and another for vertical sections and the lupus band test) and one sample taken from the nonaffected area (Figure 2). Analogous organized scalp biopsy techniques should significantly improve the quality of dermatopathological interpretation of hair loss diseases.
Treatment of AA AA is a common hair loss problem encountered by dermatologists and various therapies have been attempted to treat this condition.14,15 However, few therapies have been
B
Figure 1 Usefulness of trichoscopy (dry dermoscopy) in the diagnosis of hair loss disease. (A) Some cases of trichotillomania are barely distinguishable from alopecia areata in clinical appearance. (B) Diagnosis of trichotillomania is made by characteristic trichoscopic findings: black dots and broken hairs (arrowheads) without tapering hairs or small vellus hairs.
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Management of hair loss diseases 1
2 1
HE
HE
2
3 HE 3
DIF Figure 2 An organized scalp biopsy procedure enables more detailed and quantitative histological examination (HE) of hair loss conditions. Transverse sections can sample all hair follicles, and thus allow quantitative analysis (e.g. total hair follicle numbers, anagen/telogen ratio), while vertical sections are best at detecting the change in interface area. Comparison between affected and nonaffected lesions enables more precise histopathological interpretation. Ideally, two samples from affected lesions (one for transverse sections and another for vertical sections and direct immunofluorescent [DIF] study) and one sample from a nonaffected lesion need to be obtained.
evaluated in randomized controlled trials. Accordingly, evidenced-based therapeutic approaches are extremely limited.14,15 Although the evidence is not yet conclusive, intralesional corticosteroid injection and contact immunotherapy are considered effective therapies for AA14,15 and are listed in major guidelines, including those of the National Alopecia Areata Foundation in the USA (http://www.naaf. org/site/PageServer). Although both therapies are satisfactorily effective in many AA cases, cases with rapidly progressive AA or persisting AA totalis/universalis are frequently refractory to those treatments. Recently, Nakajima et al16 reported that pulse corticosteroid therapy is effective for recent-onset, severe cases of AA (duration of AA ≤ 6 months from the onset of active hair loss). In their study, 59.4% of the recent-onset group responded well (> 75% regrowth of alopecia lesions). Notably, 88.0% of recent-onset AA patients with less severe disease ≤ 50% hair loss) and 21.4% of recent-onset cases with 100% hair loss showed a favorable response. No serious side effects were observed. However, only 15.8% of patients with > 6 months duration satisfactorily responded. Pathologically, perifollicular inflammation is apparent only in the acute phase of AA. In the chronic phase of AA, telogen hair follicles surrounded by moderate to little cell infiltration are predominantly observed.1,9 The difference in response against glucocorticoid pulse therapy between recent-onset and longlasting AA cases could be explained by a direct suppressive effect of corticosteroids against active inflammation in acute severe AA cases. Systemic corticosteroid therapy for AA is controversial. However, considering that the total dose of corticosteroids is smaller in pulse therapy than that in conventional systemic oral administration in the long term, pulse
therapy may be beneficial for recent-onset rapidly progressing AA cases.16 Ito et al17 reported another potential therapy for intractable AA. In their study, alopecia totalis and universalis patients received combination therapy with oral psoralen plus ultraviolet A (starting from half of the minimal phototoxic dose of 20 mg methoxsalen/day, 5 days per week) and oral prednisolone (20 mg/day for 4 weeks and then decreased to 5 mg/ week). All of the six alopecia totalis patients and one of the three alopecia universalis patients demonstrated remarkable hair regrowth 3 months after the combination therapy was initiated. The treatment was well-tolerated and no severe side effects were noted. In the responders, the number of perifollicular infiltrating lymphocytes was decreased with an increase in the percentage of CD4 + CD25 + FOX3 + regulatory T cells, suggesting that the effect of the combination therapy could be explained by an immunomodulatory effect.17 Despite its efficacy, the treatment mostly requires hospitalization to avoid ophthalmologic complications.17 We adopted the principle of their combination therapy and modified the protocol, so that the treatment could be performed for outpatients. We replaced oral psoralen plus ultraviolet A with the psoralen plus ultraviolet A-turban method, which has been previously reported as an efficient therapy for AA,18 and combined it with oral administration of prednisolone. Satisfactory hair regrowth was often achieved in persisting alopecia totalis and universalis cases (Figure 3). Low-dose systemic corticosteroids (about 5 mg/day) are mostly required to maintain an effect. A double-blind clinical study has not been conducted for this therapy. In addition, the number of accumulated cases is still not large enough to give statistical significance. Therefore, a definitive conclusion
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Pre-treatment
After-treatment
Figure 3 Effect of psoralen ultraviolet A (PUVA)-turban and systemic corticosteroid therapy. Satisfactory hair regrowth was observed in a persistent alopecia totalis patient.
Pre-treatment
After-treatment
Figure 4 Combination of clobetasol propionate ointment under occlusion and intralesional steroid injection yields a favorable outcome. A young female patient had been refractory to contact immunotherapy. Hair regrowth was initiated when the combination therapy was introduced.
cannot be made. However, based on our experience in the hair disease clinic, the combination therapy should be attempted when a long-lasting severe AA patient desires a treatment that has certain efficacy. Tosti et al19 reported an approach that can be easily introduced into office dermatology. In their study, alopecia totalis/ universalis patients were treated with clobetasol propionate 0.05% ointment under occlusion. Eight of the 28 severe alopecia patients responded with regrowth of terminal hairs. Despite the finding that three of the eight responders had a relapse, the finding that hair regrowth was exclusively observed on the treated half of the scalp indicated the efficacy of the remedy.19 In our clinic, we have combined intralesional corticosteroid injection and clobetasol ointment occlusive dressing therapy and have experienced a favorable response in some severe AA cases (Figure 4). Recently, the potential role of antihistamines in AA treatment has been reported.20–22 The incidence of AA is higher in individuals with an atopic background.23 An increase in infiltrating eosinophils and mast cells has been also described in AA lesions.24,25 These observations suggest that
antihistamines could be useful as medications for AA. Inui et al22 have reported that addition of oral fexofenadine hydrochloride to contact immunotherapy improves the outcome of the treatment.22 In an experimental evaluation of the efficacy of ebastine for AA, C3H/HeJ AA active disease model mice26 were orally administered either ebastine or vehicle.23 Interestingly, hair regrowth was observed only in ebastine-treated mice (Figure 523). Although the exact mechanism and efficacy of antihistamines in AA treatment are yet to be elucidated, these findings are supportive for antihistamines being considered as supportive medications, at least for AA patients with an atopic background.23 Some cases of severely affected, rapidly progressing AA spontaneously recover without intensive therapy.27 This subset of AA, named as “acute diffuse and total alopecia of the female scalp” (ADTAFS), is mostly observed in young female patients.27,28 The condition is characterized clinically by rapid hair loss progressing to total baldness with subsequent rapid recovery, and pathologically by perifollicular eosinophilic cell infiltrate.27 The prognosis of ADTAFS patients is mostly favorable.28 A similar regression has also
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with telogen effluvium.32 It is controversial whether iron or zinc deficiency can increase the incidence of telogen effluvium.33–35 We have experienced several chronic telogen effluvium cases with low serum levels of iron or zinc. Supplementation of these elements terminated hair loss in those cases, suggesting that low iron or zinc levels could have been responsible for hair loss in those individuals. Iron and zinc levels cannot be routinely measured in telogen effluvium cases, but may deserve consideration, especially in those prone to lose iron or zinc, including hypermenorrhea, myoma or inflammatory bowel disease patients. Control
Ebastine
Understanding scarring alopecia Figure 5 Experimental evaluation of the efficacy of antihistamines as a medication for alopecia areata (AA). Pairs of C3H/HeJ AA model mice with the same extent of alopecic lesions were treated with either oral ebastine or vehicle. Improvement of AA lesions was observed only in ebastine-treated mice, suggesting the efficacy of ebastine as a supportive medication for AA (for details, see Ohyama et al23).
It has been widely accepted that topical minoxidil and oral finasteride provide effective remedies for AGA. However, oral finasteride administration does not always yield a satisfactory outcome in AGA cases. Because pharmacological effects of minoxidil and finasteride on AGA are distinct, a possible strategy to enhance the efficacy of AGA treatment is to combine both therapeutic approaches. Indeed, favorable responses of such combination therapy have already been reported.29,30 Another promising remedy for AGA is oral administration of dutasteride. Dutasteride is a dual blocker of 5 alpha-reductase type 1 and 2.31 Although not definitive, a previous clinical trial has suggested an advantage of dutasteride compared with finasteride.31 Further accumulation of cases is necessary to draw a definitive conclusion; however, dutasteride may be a future alternative for AGA cases refractory to oral finasteride therapy.
Recent advances in hair follicle stem cell biology have enabled a better understanding of the pathogenesis of scarring alopecia.36–38 Hair follicles are self-renewing tissues and the presence of tissue specific stem cells has been speculated. Using a label-retaining cell technique to detect slowcycling stem cells in vivo, hair follicle stem cells were detected in the bulge region of hair follicles.39–41 The bulge region is a contiguous portion of the outer root sheath, which provides the insertion point of the arrector pili muscle.39 One of the most distinctive histopathological features of scarring alopecia, including cutaneous lupus erythematosus and lichen planopilaris (Figure 6A), is cell infiltration involving the bulge region of the hair follicle (Figure 6B).10 This characteristic inflammatory change is considered to impair hair follicle stem cells with a resultant permanent hair loss (Figure 6C).36–38 Thus it is critically important to diagnose scarring alopecia as soon as possible and initiate anti-inflammatory therapy, such as local corticosteroid injection, before the stem cells are irreversibly damaged. Biopsy is particularly important in scarring alopecia to confirm the diagnosis and to detect latent ongoing inflammation in clinically uninvolved regions. Treatment options for scarring alopecia are extremely limited. However, it should be noted that, in addition to medications, surgical procedures such as hair transplantation and excision can provide satisfactory results in stable primary lymphocytic and secondary (post burn or traumatic) scarring alopecia.42,43 Recent studies44,45 have suggested the downregulation of some bulge markers or that PPAR-gamma plays a role in the pathogenesis of scarring alopecia. Modulation of those targets, e.g. administration of a peroxisome proliferatoractivated receptor gamma agonist,46 presents a possible strategy to control this intractable form of alopecia.
Laboratory tests for telogen effluvium
Conclusion and future directions
It has been widely accepted that laboratory tests for thyroid disease or collagen diseases should be considered for patients
As described above, remarkable advances have been made in the understanding of the pathophysiology of hair loss
been found in senile male cases.28 Thus the condition may not be restricted to females.28 These observations reinforce that an aggressive treatment is not always necessary for severe AA cases. Patients with ADTAFS are often barely distinguishable just based on clinical presentations. However, careful course observation, instead of immediate introduction of aggressive therapy, is recommended once ADTAFS is considered as a differential diagnosis.
Treatment of AGA
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A C Cell infiltration
B
Damage to bulge stem cells
Figure 6 Recent understanding of the pathogenesis of scarring alopecia. (A) Clinical manifestation of scarring alopecia (lichen planopilaris). (B) Dense cell infiltration surrounding the bulge area. (C) Destruction of bulge stem cells results in permanent hair loss.
disorders. Effective treatments for previously uncontrollable forms of alopecia (finasteride for AGA is the best example) have become available. However, remedies for various forms of refractory alopecia still need to be developed. The recent progress in regenerative medicine and pharmacology is promising for future treatment. Bioengineering of hair follicles combined with hair transplantation could enable the treatment of stable but broad scarring alopecia. Likewise, immune modulation by biologics or small molecules may provide efficient treatment for severe AA.
Acknowledgments I would like to thank Dr Wei-Ming Wang (Department of Dermatology, Tri-Service General Hospital, National Defense Medical Center) and all the board members of the Taiwanese Dermatological Association for their encouragement and support.
2. 3. 4. 5. 6.
7.
8.
9. 10. 11.
12.
References
13.
1.
14.
Alkhalifah A, Alsantali A, Wang E, et al. Alopecia areata update: part I. Clinical picture, histopathology, and pathogenesis. J Am Acad Dermatol 2010;62:177–88, quiz 189–90.
Bolduc C, Shapiro J. Management of androgenetic alopecia. Am J Clin Dermatol 2000;1:151–8. Braun RP, Rabinovitz HS, Oliviero M, et al. Dermoscopy of pigmented skin lesions. J Am Acad Dermatol 2005;52:109–21. Inui S, Nakajima T, Itami S. Dry dermoscopy in clinical treatment of alopecia areata. J Dermatol 2007;34:635–9. Inui S, Nakajima T, Itami S. Scalp dermoscopy of androgenetic alopecia in Asian people. J Dermatol 2009;36:82–5. Inui S, Nakajima T, Nakagawa K, Itami S. Clinical significance of dermoscopy in alopecia areata: analysis of 300 cases. Int J Dermatol 2008;47:688–93. Lee DY, Lee JH, Yang JM, Lee ES. The use of dermoscopy for the diagnosis of trichotillomania. J Eur Acad Dermatol Venereol 2009;23:731–2. Headington JT. Transverse microscopic anatomy of the human scalp. A basis for a morphometric approach to disorders of the hair follicle. Arch Dermatol 1984;120:449–56. Whiting DA. Histopathology of alopecia areata in horizontal sections of scalp biopsies. J Invest Dermatol 1995;104:26–7S. Sperling LC. An Atlas of Hair Pathology With Clinical Correlations. New York: Parthenon, 2003. Frishberg DP, Sperling LC, Guthrie VM. Transverse scalp sections: a proposed method for laboratory processing. J Am Acad Dermatol 1996;35:220–2. Boer A, Hoene K. Transverse sections for diagnosis of alopecia? Am J Dermatopathol 2005;27:348–52. Elston DM. Vertical vs. transverse sections: both are valuable in the evaluation of alopecia. Am J Dermatopathol 2005;27:353–6. MacDonald Hull SP, Wood ML, Hutchinson PE, et al. Guidelines for the management of alopecia areata. Br J Dermatol 2003;149: 692–9.
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Management of hair loss diseases 15.
16.
17.
18.
19.
20.
21. 22.
23.
24. 25.
26. 27.
28.
29.
30.
Alkhalifah A, Alsantali A, Wang E, et al. Alopecia areata update: part II. Treatment. J Am Acad Dermatol 2010;62:191–202, quiz 203–4. Nakajima T, Inui S, Itami S. Pulse corticosteroid therapy for alopecia areata: study of 139 patients. Dermatology 2007;215: 320–4. Ito T, Aoshima M, Ito N, et al. Combination therapy with oral PUVA and corticosteroid for recalcitrant alopecia areata. Arch Dermatol Res 2009;301:373–80. Behrens-Williams SC, Leiter U, Schiener R, et al. The PUVAturban as a new option of applying a dilute psoralen solution selectively to the scalp of patients with alopecia areata. J Am Acad Dermatol 2001;44:248–52. Tosti A, Piraccini BM, Pazzaglia M, Vincenzi C. Clobetasol propionate 0.05% under occlusion in the treatment of alopecia totalis/universalis. J Am Acad Dermatol 2003;49:96–8. Ogawa H, Imai R, Nishiyama S, et al. The effect of an anti-allergic drug on the disease acitivity of alopecia areata. Skin Research 1994;36:60–68. [In Japanese] Yoshizawa Y, Kawana S. Efficacy of ebasitne in the treatment of alopecia areata. Jpn J Dermatol 2005;115:1473–80. Inui S, Nakajima T, Toda N, Itami S. Fexofenadine hydrochloride enhances the efficacy of contact immunotherapy for extensive alopecia areata: retrospective analysis of 121 cases. J Dermatol 2009;36:323–7. Ohyama M, Shimizu A, Tanaka K, Amagai M. Experimental evaluation of ebastine, a second-generation anti-histamine, as a supportive medication for alopecia areata. J Dermatol Sci 2010;58:154–7. Tanii T, Okada T, Fukai K, et al. Increase of mast cells in the alopecia lesion of mice. Acta Derm Venereol 1985;65:64–6. Elston DM, McCollough ML, Bergfeld WF, et al. Eosinophils in fibrous tracts and near hair bulbs: a helpful diagnostic feature of alopecia areata. J Am Acad Dermatol 1997;37:101–6. Sundberg JP, Cordy WR, King LE Jr. Alopecia areata in aging C3H/HeJ mice. J Invest Dermatol 1994;102:847–56. Sato-Kawamura M, Aiba S, Tagami H. Acute diffuse and total alopecia of the female scalp. A new subtype of diffuse alopecia areata that has a favorable prognosis. Dermatology 2002;205: 367–73. Lew BL, Shin MK, Sim WY. Acute diffuse and total alopecia: a new subtype of alopecia areata with a favorable prognosis. J Am Acad Dermatol 2009;60:85–93. Diani AR, Mulholland MJ, Shull KL, et al. Hair growth effects of oral administration of finasteride, a steroid 5 alpha-reductase inhibitor, alone and in combination with topical minoxidil in the balding stumptail macaque. J Clin Endocrinol Metab 1992;74: 345–50. Khandpur S, Suman M, Reddy BS. Comparative efficacy of various treatment regimens for androgenetic alopecia in men. J Dermatol 2002;29:489–98.
31.
32. 33. 34.
35.
36. 37.
38.
39.
40.
41.
42. 43. 44.
45.
46.
Olsen EA, Hordinsky M, Whiting D, et al. The importance of dual 5-alpha reductase inhibition in the treatment of male pattern hair loss: results of a randomized placebo-controlled study of dutasteride versus finasteride. J Am Acad Dermatol 2006;55: 1014–23. Harrison S, Sinclair R. Telogen effluvium. Clin Exp Dermatol 2002; 27:389–5. Olsen EA. Iron deficiency and hair loss: the jury is still out. J Am Acad Dermatol 2006;54:903–6. Trost LB, Bergfeld WF, Calogeras E. The diagnosis and treatment of iron deficiency and its potential relationship to hair loss. J Am Acad Dermatol 2006;54:824–44. Park H, Kim CW, Kim SS, Park CW. The therapeutic effect and the changed serum zinc level after zinc supplementation in alopecia areata patients who had a low serum zinc level. Ann Dermatol 2009;21:142–6. Cotsarelis G, Millar SE. Towards a molecular understanding of hair loss and its treatment. Trends Mol Med 2001;7:293–301. Mobini N, Tam S, Kamino H. Possible role of the bulge region in the pathogenesis of inflammatory scarring alopecia: lichen planopilaris as the prototype. J Cutan Pathol 2005;32:675–9. Harries MJ, Meyer KC, Chaudhry IH, et al. Does collapse of immune privilege in the hair-follicle bulge play a role in the pathogenesis of primary cicatricial alopecia? Clin Exp Dermatol 2009;3:3. Cotsarelis G, Sun TT, Lavker RM. Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell 1990;61: 1329–37. Lyle S, Christofidou-Solomidou M, Liu Y, et al. The C8/144B monoclonal antibody recognizes cytokeratin 15 and defines the location of human hair follicle stem cells. J Cell Sci 1998;111(Pt 21): 3179–88. Ohyama M, Terunuma A, Tock CL, et al. Characterization and isolation of stem cell-enriched human hair follicle bulge cells. J Clin Invest 2006;116:249–60. Finner AM, Otberg N, Shapiro J. Secondary cicatricial and other permanent alopecias. Dermatol Ther 2008;21:279–94. Unger W, Unger R, Wesley C. The surgical treatment of cicatricial alopecia. Dermatol Ther 2008;21:295–311. Al-Refu K, Edward S, Ingham E, Goodfield M. Expression of hair follicle stem cells detected by cytokeratin 15 stain: implications for pathogenesis of the scarring process in cutaneous lupus erythematosus. Br J Dermatol 2009;160:1188–96. Karnik P, Tekeste Z, McCormick TS, et al. Hair follicle stem cellspecific PPARgamma deletion causes scarring alopecia. J Invest Dermatol 2009;129:1243–57. Mirmirani P, Karnik P. Lichen planopilaris treated with a peroxisome proliferator-activated receptor gamma agonist. Arch Dermatol 2009;145:1363–6.
R EVI EW ARTIC LE
Management of hair loss diseases Manabu Ohyama* Department of Dermatology, Keio University School of Medicine, Tokyo, Japan
KEY WO R D S
AB S T R ACT
Alopecia areata Androgenetic alopecia Bulge stem cells Scarring alopecia Telogen effluvium Transverse section Trichoscopy
The treatment of hair loss diseases is sometimes difficult because of insufficient efficacy and limited options. However, recent advances in understanding of the pathophysiology and development of new remedies have improved the treatment of refractory hair loss conditions. In this article, an update on the management of hair loss diseases is provided, especially focusing on recently reported therapeutic approaches for alopecia areata (AA). An accurate diagnosis is indispensable to optimize treatment. Dry dermoscopy represents new diagnostic techniques, which could enable the differentiation of barely indistinguishable alopecias, e.g. AA and trichotillomania. An organized scalp biopsy adopting both vertical and transverse sectioning approaches also provides a deep insight into the pathophysiology of ongoing alopecias. Among various treatments for AA, intraregional corticosteroid and contact immunotherapy have been recognized as first-line therapies. However, some AA cases are refractory to both treatments. Recent studies have demonstrated the efficacy of pulse corticosteroid therapy or the combination of oral psoralen ultraviolet A therapy and systemic corticosteroids for severe AA. Previous clinical observations have suggested the potential role of antihistamines as supportive medications for AA. Experimental evaluation using AA model mice further supports their effectiveness in AA treatment. Finasteride opens up new possibilities for the treatment of androgenetic alopecia. For androgenetic alopecia patients refractory to finasteride, the combination of finasteride with topical minoxidil or the administration of dutasteride, another 5 alpha-reductase inhibitor, may provide better outcomes. Scarring alopecia is the most difficult form of hair loss disorder to treat. The bulge stem cell area is destroyed by unnecessary immune reactions with resultant permanent loss of hair follicle structures in scarring alopecia. Currently, treatment options for this hair loss disorder are extremely limited. The development of effective therapies for this form of intractable alopecia represents an important issue to be resolved. Copyright © 2010, Taiwanese Dermatological Association. Published by Elsevier Taiwan LLC. All rights reserved.
Introduction Hair loss diseases, represented by alopecia areata (AA) or androgenetic alopecia (AGA), are relatively common dermatological problems encountered in daily practice.1,2 Although effective therapies are readily available for some types of alopecia, treatment options for certain subsets are
*Corresponding author. Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan. E-mail: [email protected]
extremely limited with unfavorable outcomes Accordingly, attempts have been made to develop or improve therapeutic approaches for intractable alopecia. In this review, recent advances in the management of hair loss diseases, including new techniques that enable proper diagnosis, novel therapeutic approaches and future perspectives are summarized. Particular emphasis is placed on the treatments for severe AA. Although remarkable progress has been made in the molecular biological understanding of genetic hair loss or anomalies, these conditions are not discussed in this article because they are rare.
140
M. Ohyama
Advances in diagnostic procedures A correct diagnosis is indispensable to select and perform optimal treatment for hair loss diseases. Hair loss conditions with distinct clinical manifestations, such as typical AA and AGA, can be easily diagnosed based on the pattern of hair loss or the shape of fallen out hair shafts. However, some hair loss conditions are not diagnosable just by routine clinical evaluations. Dermoscopy is a useful device, especially for the evaluation of pigmentary lesions, including melanoma.3 The use of videodermoscopy or dry dermoscopy (dermoscopy without an immersion gel) enhances the diagnostic capacity in some hair loss conditions.4–7 Inui et al6 reported that yellow dots and short vellus hairs are the most sensitive markers of AA, while hair diameter diversity is an essential feature of AGA. Scalp dermoscopy also provides a powerful tool to differentiate clinically resembling hair loss conditions. Trichotillomania in which habitual or unconscious hair pulling causes mostly discrete alopecic patches, sometimes presents with an AA-like appearance (Figure 1A). Such lesions can be easily distinguished from AA by dermoscopy. Characteristic dermoscopic findings of trichotillomania are black dots and broken hairs without tapering hairs or small vellus hairs (Figure 1B).6,7 Dermoscopy is useful for the diagnosis of hair loss conditions as well as the evaluation of disease activity. For example, the presence of such findings as tapering hairs and short vellus hairs is correlated with AA disease activity.6 Collectively, the use of dermoscopy for the diagnosis of hair loss disorders is highly recommended. Scalp biopsy may not be included in “routine” diagnostic procedures for hair loss conditions. However, histopathological investigation of alopecic lesions is sometimes necessary to make a final diagnosis (e.g. scarring alopecia) or better understand the pathophysiology of the ongoing disease. It has
A
been reported that transverse sections of punch scalp biopsy specimens enable quantitative morphometric analysis of hair follicles.8 Factors that are indispensable for pathological interpretation of hair loss conditions, including total hair follicle number, the telogen/anagen ratio, and the ratio between terminal and vellus hairs, cannot be determined by conventional vertical sections (Figure 2).9,10 In addition, by slicing a sample into 3–4 disks (so that each disk contains infundibulum, isthmus, suprabulbar and bulbar regions) and embedding the same side down into the same cassette, several levels of hair follicles can be investigated on a single slide (Figure 2).11 Ideally, transverse sections should be prepared from both affected and unaffected sites for comparison.10 Although transverse scalp sections exceed conventional vertical sections in many aspects, some key pathological information is barely detectable by the transverse sectioning approach.12 For example, changes in the dermo-epidermal junction (interface change) cannot be appropriately assessed by the transverse approach. Thus both transverse and vertical sections are valuable in the diagnosis of hair loss disorders.13 In our hair disease clinic, a standard histopathological investigation includes two 4 mm punch biopsy samples obtained from affected lesions (one for transverse sections and another for vertical sections and the lupus band test) and one sample taken from the nonaffected area (Figure 2). Analogous organized scalp biopsy techniques should significantly improve the quality of dermatopathological interpretation of hair loss diseases.
Treatment of AA AA is a common hair loss problem encountered by dermatologists and various therapies have been attempted to treat this condition.14,15 However, few therapies have been
B
Figure 1 Usefulness of trichoscopy (dry dermoscopy) in the diagnosis of hair loss disease. (A) Some cases of trichotillomania are barely distinguishable from alopecia areata in clinical appearance. (B) Diagnosis of trichotillomania is made by characteristic trichoscopic findings: black dots and broken hairs (arrowheads) without tapering hairs or small vellus hairs.
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2 1
HE
HE
2
3 HE 3
DIF Figure 2 An organized scalp biopsy procedure enables more detailed and quantitative histological examination (HE) of hair loss conditions. Transverse sections can sample all hair follicles, and thus allow quantitative analysis (e.g. total hair follicle numbers, anagen/telogen ratio), while vertical sections are best at detecting the change in interface area. Comparison between affected and nonaffected lesions enables more precise histopathological interpretation. Ideally, two samples from affected lesions (one for transverse sections and another for vertical sections and direct immunofluorescent [DIF] study) and one sample from a nonaffected lesion need to be obtained.
evaluated in randomized controlled trials. Accordingly, evidenced-based therapeutic approaches are extremely limited.14,15 Although the evidence is not yet conclusive, intralesional corticosteroid injection and contact immunotherapy are considered effective therapies for AA14,15 and are listed in major guidelines, including those of the National Alopecia Areata Foundation in the USA (http://www.naaf. org/site/PageServer). Although both therapies are satisfactorily effective in many AA cases, cases with rapidly progressive AA or persisting AA totalis/universalis are frequently refractory to those treatments. Recently, Nakajima et al16 reported that pulse corticosteroid therapy is effective for recent-onset, severe cases of AA (duration of AA ≤ 6 months from the onset of active hair loss). In their study, 59.4% of the recent-onset group responded well (> 75% regrowth of alopecia lesions). Notably, 88.0% of recent-onset AA patients with less severe disease ≤ 50% hair loss) and 21.4% of recent-onset cases with 100% hair loss showed a favorable response. No serious side effects were observed. However, only 15.8% of patients with > 6 months duration satisfactorily responded. Pathologically, perifollicular inflammation is apparent only in the acute phase of AA. In the chronic phase of AA, telogen hair follicles surrounded by moderate to little cell infiltration are predominantly observed.1,9 The difference in response against glucocorticoid pulse therapy between recent-onset and longlasting AA cases could be explained by a direct suppressive effect of corticosteroids against active inflammation in acute severe AA cases. Systemic corticosteroid therapy for AA is controversial. However, considering that the total dose of corticosteroids is smaller in pulse therapy than that in conventional systemic oral administration in the long term, pulse
therapy may be beneficial for recent-onset rapidly progressing AA cases.16 Ito et al17 reported another potential therapy for intractable AA. In their study, alopecia totalis and universalis patients received combination therapy with oral psoralen plus ultraviolet A (starting from half of the minimal phototoxic dose of 20 mg methoxsalen/day, 5 days per week) and oral prednisolone (20 mg/day for 4 weeks and then decreased to 5 mg/ week). All of the six alopecia totalis patients and one of the three alopecia universalis patients demonstrated remarkable hair regrowth 3 months after the combination therapy was initiated. The treatment was well-tolerated and no severe side effects were noted. In the responders, the number of perifollicular infiltrating lymphocytes was decreased with an increase in the percentage of CD4 + CD25 + FOX3 + regulatory T cells, suggesting that the effect of the combination therapy could be explained by an immunomodulatory effect.17 Despite its efficacy, the treatment mostly requires hospitalization to avoid ophthalmologic complications.17 We adopted the principle of their combination therapy and modified the protocol, so that the treatment could be performed for outpatients. We replaced oral psoralen plus ultraviolet A with the psoralen plus ultraviolet A-turban method, which has been previously reported as an efficient therapy for AA,18 and combined it with oral administration of prednisolone. Satisfactory hair regrowth was often achieved in persisting alopecia totalis and universalis cases (Figure 3). Low-dose systemic corticosteroids (about 5 mg/day) are mostly required to maintain an effect. A double-blind clinical study has not been conducted for this therapy. In addition, the number of accumulated cases is still not large enough to give statistical significance. Therefore, a definitive conclusion
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Pre-treatment
After-treatment
Figure 3 Effect of psoralen ultraviolet A (PUVA)-turban and systemic corticosteroid therapy. Satisfactory hair regrowth was observed in a persistent alopecia totalis patient.
Pre-treatment
After-treatment
Figure 4 Combination of clobetasol propionate ointment under occlusion and intralesional steroid injection yields a favorable outcome. A young female patient had been refractory to contact immunotherapy. Hair regrowth was initiated when the combination therapy was introduced.
cannot be made. However, based on our experience in the hair disease clinic, the combination therapy should be attempted when a long-lasting severe AA patient desires a treatment that has certain efficacy. Tosti et al19 reported an approach that can be easily introduced into office dermatology. In their study, alopecia totalis/ universalis patients were treated with clobetasol propionate 0.05% ointment under occlusion. Eight of the 28 severe alopecia patients responded with regrowth of terminal hairs. Despite the finding that three of the eight responders had a relapse, the finding that hair regrowth was exclusively observed on the treated half of the scalp indicated the efficacy of the remedy.19 In our clinic, we have combined intralesional corticosteroid injection and clobetasol ointment occlusive dressing therapy and have experienced a favorable response in some severe AA cases (Figure 4). Recently, the potential role of antihistamines in AA treatment has been reported.20–22 The incidence of AA is higher in individuals with an atopic background.23 An increase in infiltrating eosinophils and mast cells has been also described in AA lesions.24,25 These observations suggest that
antihistamines could be useful as medications for AA. Inui et al22 have reported that addition of oral fexofenadine hydrochloride to contact immunotherapy improves the outcome of the treatment.22 In an experimental evaluation of the efficacy of ebastine for AA, C3H/HeJ AA active disease model mice26 were orally administered either ebastine or vehicle.23 Interestingly, hair regrowth was observed only in ebastine-treated mice (Figure 523). Although the exact mechanism and efficacy of antihistamines in AA treatment are yet to be elucidated, these findings are supportive for antihistamines being considered as supportive medications, at least for AA patients with an atopic background.23 Some cases of severely affected, rapidly progressing AA spontaneously recover without intensive therapy.27 This subset of AA, named as “acute diffuse and total alopecia of the female scalp” (ADTAFS), is mostly observed in young female patients.27,28 The condition is characterized clinically by rapid hair loss progressing to total baldness with subsequent rapid recovery, and pathologically by perifollicular eosinophilic cell infiltrate.27 The prognosis of ADTAFS patients is mostly favorable.28 A similar regression has also
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with telogen effluvium.32 It is controversial whether iron or zinc deficiency can increase the incidence of telogen effluvium.33–35 We have experienced several chronic telogen effluvium cases with low serum levels of iron or zinc. Supplementation of these elements terminated hair loss in those cases, suggesting that low iron or zinc levels could have been responsible for hair loss in those individuals. Iron and zinc levels cannot be routinely measured in telogen effluvium cases, but may deserve consideration, especially in those prone to lose iron or zinc, including hypermenorrhea, myoma or inflammatory bowel disease patients. Control
Ebastine
Understanding scarring alopecia Figure 5 Experimental evaluation of the efficacy of antihistamines as a medication for alopecia areata (AA). Pairs of C3H/HeJ AA model mice with the same extent of alopecic lesions were treated with either oral ebastine or vehicle. Improvement of AA lesions was observed only in ebastine-treated mice, suggesting the efficacy of ebastine as a supportive medication for AA (for details, see Ohyama et al23).
It has been widely accepted that topical minoxidil and oral finasteride provide effective remedies for AGA. However, oral finasteride administration does not always yield a satisfactory outcome in AGA cases. Because pharmacological effects of minoxidil and finasteride on AGA are distinct, a possible strategy to enhance the efficacy of AGA treatment is to combine both therapeutic approaches. Indeed, favorable responses of such combination therapy have already been reported.29,30 Another promising remedy for AGA is oral administration of dutasteride. Dutasteride is a dual blocker of 5 alpha-reductase type 1 and 2.31 Although not definitive, a previous clinical trial has suggested an advantage of dutasteride compared with finasteride.31 Further accumulation of cases is necessary to draw a definitive conclusion; however, dutasteride may be a future alternative for AGA cases refractory to oral finasteride therapy.
Recent advances in hair follicle stem cell biology have enabled a better understanding of the pathogenesis of scarring alopecia.36–38 Hair follicles are self-renewing tissues and the presence of tissue specific stem cells has been speculated. Using a label-retaining cell technique to detect slowcycling stem cells in vivo, hair follicle stem cells were detected in the bulge region of hair follicles.39–41 The bulge region is a contiguous portion of the outer root sheath, which provides the insertion point of the arrector pili muscle.39 One of the most distinctive histopathological features of scarring alopecia, including cutaneous lupus erythematosus and lichen planopilaris (Figure 6A), is cell infiltration involving the bulge region of the hair follicle (Figure 6B).10 This characteristic inflammatory change is considered to impair hair follicle stem cells with a resultant permanent hair loss (Figure 6C).36–38 Thus it is critically important to diagnose scarring alopecia as soon as possible and initiate anti-inflammatory therapy, such as local corticosteroid injection, before the stem cells are irreversibly damaged. Biopsy is particularly important in scarring alopecia to confirm the diagnosis and to detect latent ongoing inflammation in clinically uninvolved regions. Treatment options for scarring alopecia are extremely limited. However, it should be noted that, in addition to medications, surgical procedures such as hair transplantation and excision can provide satisfactory results in stable primary lymphocytic and secondary (post burn or traumatic) scarring alopecia.42,43 Recent studies44,45 have suggested the downregulation of some bulge markers or that PPAR-gamma plays a role in the pathogenesis of scarring alopecia. Modulation of those targets, e.g. administration of a peroxisome proliferatoractivated receptor gamma agonist,46 presents a possible strategy to control this intractable form of alopecia.
Laboratory tests for telogen effluvium
Conclusion and future directions
It has been widely accepted that laboratory tests for thyroid disease or collagen diseases should be considered for patients
As described above, remarkable advances have been made in the understanding of the pathophysiology of hair loss
been found in senile male cases.28 Thus the condition may not be restricted to females.28 These observations reinforce that an aggressive treatment is not always necessary for severe AA cases. Patients with ADTAFS are often barely distinguishable just based on clinical presentations. However, careful course observation, instead of immediate introduction of aggressive therapy, is recommended once ADTAFS is considered as a differential diagnosis.
Treatment of AGA
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A C Cell infiltration
B
Damage to bulge stem cells
Figure 6 Recent understanding of the pathogenesis of scarring alopecia. (A) Clinical manifestation of scarring alopecia (lichen planopilaris). (B) Dense cell infiltration surrounding the bulge area. (C) Destruction of bulge stem cells results in permanent hair loss.
disorders. Effective treatments for previously uncontrollable forms of alopecia (finasteride for AGA is the best example) have become available. However, remedies for various forms of refractory alopecia still need to be developed. The recent progress in regenerative medicine and pharmacology is promising for future treatment. Bioengineering of hair follicles combined with hair transplantation could enable the treatment of stable but broad scarring alopecia. Likewise, immune modulation by biologics or small molecules may provide efficient treatment for severe AA.
Acknowledgments I would like to thank Dr Wei-Ming Wang (Department of Dermatology, Tri-Service General Hospital, National Defense Medical Center) and all the board members of the Taiwanese Dermatological Association for their encouragement and support.
2. 3. 4. 5. 6.
7.
8.
9. 10. 11.
12.
References
13.
1.
14.
Alkhalifah A, Alsantali A, Wang E, et al. Alopecia areata update: part I. Clinical picture, histopathology, and pathogenesis. J Am Acad Dermatol 2010;62:177–88, quiz 189–90.
Bolduc C, Shapiro J. Management of androgenetic alopecia. Am J Clin Dermatol 2000;1:151–8. Braun RP, Rabinovitz HS, Oliviero M, et al. Dermoscopy of pigmented skin lesions. J Am Acad Dermatol 2005;52:109–21. Inui S, Nakajima T, Itami S. Dry dermoscopy in clinical treatment of alopecia areata. J Dermatol 2007;34:635–9. Inui S, Nakajima T, Itami S. Scalp dermoscopy of androgenetic alopecia in Asian people. J Dermatol 2009;36:82–5. Inui S, Nakajima T, Nakagawa K, Itami S. Clinical significance of dermoscopy in alopecia areata: analysis of 300 cases. Int J Dermatol 2008;47:688–93. Lee DY, Lee JH, Yang JM, Lee ES. The use of dermoscopy for the diagnosis of trichotillomania. J Eur Acad Dermatol Venereol 2009;23:731–2. Headington JT. Transverse microscopic anatomy of the human scalp. A basis for a morphometric approach to disorders of the hair follicle. Arch Dermatol 1984;120:449–56. Whiting DA. Histopathology of alopecia areata in horizontal sections of scalp biopsies. J Invest Dermatol 1995;104:26–7S. Sperling LC. An Atlas of Hair Pathology With Clinical Correlations. New York: Parthenon, 2003. Frishberg DP, Sperling LC, Guthrie VM. Transverse scalp sections: a proposed method for laboratory processing. J Am Acad Dermatol 1996;35:220–2. Boer A, Hoene K. Transverse sections for diagnosis of alopecia? Am J Dermatopathol 2005;27:348–52. Elston DM. Vertical vs. transverse sections: both are valuable in the evaluation of alopecia. Am J Dermatopathol 2005;27:353–6. MacDonald Hull SP, Wood ML, Hutchinson PE, et al. Guidelines for the management of alopecia areata. Br J Dermatol 2003;149: 692–9.
145
Management of hair loss diseases 15.
16.
17.
18.
19.
20.
21. 22.
23.
24. 25.
26. 27.
28.
29.
30.
Alkhalifah A, Alsantali A, Wang E, et al. Alopecia areata update: part II. Treatment. J Am Acad Dermatol 2010;62:191–202, quiz 203–4. Nakajima T, Inui S, Itami S. Pulse corticosteroid therapy for alopecia areata: study of 139 patients. Dermatology 2007;215: 320–4. Ito T, Aoshima M, Ito N, et al. Combination therapy with oral PUVA and corticosteroid for recalcitrant alopecia areata. Arch Dermatol Res 2009;301:373–80. Behrens-Williams SC, Leiter U, Schiener R, et al. The PUVAturban as a new option of applying a dilute psoralen solution selectively to the scalp of patients with alopecia areata. J Am Acad Dermatol 2001;44:248–52. Tosti A, Piraccini BM, Pazzaglia M, Vincenzi C. Clobetasol propionate 0.05% under occlusion in the treatment of alopecia totalis/universalis. J Am Acad Dermatol 2003;49:96–8. Ogawa H, Imai R, Nishiyama S, et al. The effect of an anti-allergic drug on the disease acitivity of alopecia areata. Skin Research 1994;36:60–68. [In Japanese] Yoshizawa Y, Kawana S. Efficacy of ebasitne in the treatment of alopecia areata. Jpn J Dermatol 2005;115:1473–80. Inui S, Nakajima T, Toda N, Itami S. Fexofenadine hydrochloride enhances the efficacy of contact immunotherapy for extensive alopecia areata: retrospective analysis of 121 cases. J Dermatol 2009;36:323–7. Ohyama M, Shimizu A, Tanaka K, Amagai M. Experimental evaluation of ebastine, a second-generation anti-histamine, as a supportive medication for alopecia areata. J Dermatol Sci 2010;58:154–7. Tanii T, Okada T, Fukai K, et al. Increase of mast cells in the alopecia lesion of mice. Acta Derm Venereol 1985;65:64–6. Elston DM, McCollough ML, Bergfeld WF, et al. Eosinophils in fibrous tracts and near hair bulbs: a helpful diagnostic feature of alopecia areata. J Am Acad Dermatol 1997;37:101–6. Sundberg JP, Cordy WR, King LE Jr. Alopecia areata in aging C3H/HeJ mice. J Invest Dermatol 1994;102:847–56. Sato-Kawamura M, Aiba S, Tagami H. Acute diffuse and total alopecia of the female scalp. A new subtype of diffuse alopecia areata that has a favorable prognosis. Dermatology 2002;205: 367–73. Lew BL, Shin MK, Sim WY. Acute diffuse and total alopecia: a new subtype of alopecia areata with a favorable prognosis. J Am Acad Dermatol 2009;60:85–93. Diani AR, Mulholland MJ, Shull KL, et al. Hair growth effects of oral administration of finasteride, a steroid 5 alpha-reductase inhibitor, alone and in combination with topical minoxidil in the balding stumptail macaque. J Clin Endocrinol Metab 1992;74: 345–50. Khandpur S, Suman M, Reddy BS. Comparative efficacy of various treatment regimens for androgenetic alopecia in men. J Dermatol 2002;29:489–98.
31.
32. 33. 34.
35.
36. 37.
38.
39.
40.
41.
42. 43. 44.
45.
46.
Olsen EA, Hordinsky M, Whiting D, et al. The importance of dual 5-alpha reductase inhibition in the treatment of male pattern hair loss: results of a randomized placebo-controlled study of dutasteride versus finasteride. J Am Acad Dermatol 2006;55: 1014–23. Harrison S, Sinclair R. Telogen effluvium. Clin Exp Dermatol 2002; 27:389–5. Olsen EA. Iron deficiency and hair loss: the jury is still out. J Am Acad Dermatol 2006;54:903–6. Trost LB, Bergfeld WF, Calogeras E. The diagnosis and treatment of iron deficiency and its potential relationship to hair loss. J Am Acad Dermatol 2006;54:824–44. Park H, Kim CW, Kim SS, Park CW. The therapeutic effect and the changed serum zinc level after zinc supplementation in alopecia areata patients who had a low serum zinc level. Ann Dermatol 2009;21:142–6. Cotsarelis G, Millar SE. Towards a molecular understanding of hair loss and its treatment. Trends Mol Med 2001;7:293–301. Mobini N, Tam S, Kamino H. Possible role of the bulge region in the pathogenesis of inflammatory scarring alopecia: lichen planopilaris as the prototype. J Cutan Pathol 2005;32:675–9. Harries MJ, Meyer KC, Chaudhry IH, et al. Does collapse of immune privilege in the hair-follicle bulge play a role in the pathogenesis of primary cicatricial alopecia? Clin Exp Dermatol 2009;3:3. Cotsarelis G, Sun TT, Lavker RM. Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell 1990;61: 1329–37. Lyle S, Christofidou-Solomidou M, Liu Y, et al. The C8/144B monoclonal antibody recognizes cytokeratin 15 and defines the location of human hair follicle stem cells. J Cell Sci 1998;111(Pt 21): 3179–88. Ohyama M, Terunuma A, Tock CL, et al. Characterization and isolation of stem cell-enriched human hair follicle bulge cells. J Clin Invest 2006;116:249–60. Finner AM, Otberg N, Shapiro J. Secondary cicatricial and other permanent alopecias. Dermatol Ther 2008;21:279–94. Unger W, Unger R, Wesley C. The surgical treatment of cicatricial alopecia. Dermatol Ther 2008;21:295–311. Al-Refu K, Edward S, Ingham E, Goodfield M. Expression of hair follicle stem cells detected by cytokeratin 15 stain: implications for pathogenesis of the scarring process in cutaneous lupus erythematosus. Br J Dermatol 2009;160:1188–96. Karnik P, Tekeste Z, McCormick TS, et al. Hair follicle stem cellspecific PPARgamma deletion causes scarring alopecia. J Invest Dermatol 2009;129:1243–57. Mirmirani P, Karnik P. Lichen planopilaris treated with a peroxisome proliferator-activated receptor gamma agonist. Arch Dermatol 2009;145:1363–6.