Management of hair loss diseases Manabu Ohyama*

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.
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.
141
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
142
M. Ohyama
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
143
Management of hair loss diseases
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
144
M. Ohyama
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.
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