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Irritants
for the treatment of alopecia areata
Alopecia areata is characterized by phases of hair loss and hair
re-growth. The positive aspect of alopecia areata is that, though
the follicular growth is halted, arrested by the action
of lymphocytic
infiltrates
in and around the bulb-region, the hair follicle itself is not
destroyed. Hair loss comes about due to severe disruption of the
hair follicle and its growth cycle, but the basic components the
hair follicles need to regenerate remain in place. The lymphcytic
infiltrate acts to inhibit cell proliferation and hair fiber construction
in the hair follicles. It also pushes the hair follicles into
prolgned states of telogen where the hair follicle is inactive.
The inflammatory infiltrates only target anagen, growing hair
follicles, telogen follicles are not affected. However, if hair
follicles try to retrun from a telogen state to an anagen state
and the aloepcia areata is still active then the hair follicles
are retargeted by the immune cells pushing the hair follicles
back into a telogen state again. This analysis of the alopecia
areata condition indicates that it is a reversible hair loss disorder.
At
times when the attack is not severe, the disease heals on its
own. However, when the disease persists and the condition deteriorates,
treatment is necessary to bring back
or reinstate a state of normalcy or at least to override the inflmmatory
activity. One treatment apporach involves using irritant chemicals.
Irritants to treat alopecia areata have been around for a couple
of thousand years or so. Mustard seed poultice or burnt papyrus
rubbed into the scalp were used in the ancient middle east. Various
irritants and other treatments have been employed to combat alopecia
areata in western medicine. Most were used before modern clinical
trials were instigated. They included a wide range of products
such as ammonia, carbolic acid (Watson 1864), iodine (Roxburgh
1950), chrysarobin (Kinnear 1939), croton oil, capsicum, or formaldehyde
in solution (Ormsby 1948). These treatments were employed to extensively
irritate the scalp (Roxburgh 1950). Sometimes the compounds were
used in conjunction with UV light from the sun or artificial sources
to further promote their activity (Kinnear 1939, Savill 1939).
Many of these therapies are not considered viable options today
because they may have serious adverse, sometimes irreversible,
side effects. However, a few irritant treatment approaches are still
in use today in some clinics.
With high chances of all alopecia areata conditions continuing
over a prolonged period, the apposite treatment has to be a long-term
treatment devoid of any troublesome
side effects. Judged from this angle, anthralin and nitrogen mustard
(mechlorethamine) appear to be the most effective topical irritant
modalities with limited side effect risk. As efficient topical
applications, they seep through the stratum
corneum, the epidermal & dermal layers and enter the subcutaneous
fat layer. The irritant chemcials disrupt the cell activity and
promote inflammation and this change in skin status enables hair
regrowth. Treatment studies using anthralin and nitrogen mustard
on animals (rat and mouse alopecia areata models) have helped
establish the
cellular and molecular mechanisms of the therapeutic effects.
While the cellular mechanisms target lymphocytic infiltrates,
the molecular
mechanisms bring about specific cytokine (a class of immunoregulatory
proteins that are released by cells especially of the immune system)
changes that are more favorable for hair growth.
A discussion on the roles of anthralin and nitrogen mustard
(supported by treatment case studies) follows in the next sections.
Alopecia areata involves episodes of hair loss and hair re-growth
(symptoms of disease relapse and remission) and the best way to
determine
therapeutic success is to treat every patient only on one half
of the scalp (with the treating agent and the other with placebo).
Keeping this in view, most of the human model treatment studies
on anthralin and nitrogen mustard have been double blind, placebo
controlled studies.
Non
specific irritants: anthralin
While there are many irritating chemicals known, only a few
have been found effective in treating alopecia areata. Fewer still
are in common use today. However, the irritant anthralin is still
available for alopecia areata treatment from some dermatologists.
Anthralin is available in different concentrations and formulations
although typically a 0.5% anthralin concentration in a liquid
or cream base is used (often with the trade name Dithranol or
Drithocreme on the tube). The cream is applied regularly and then
washed away after a period
of time.
Frequently
the cream is washed off with the aid of a shampoo that contains
zinc pyrithione. The rate of irritant application and the exposure
time varies depending on how the dermatologist gauges the inflammatory
response each patient has to the cream. The response rate to anthralin
treatment can be quite variable from person to person so the specific
treatment approach has to be tailored to each individual. A hair
regrowth success rate of up to 67% has been indicated for
anthralin (Schmoeckel 1979, Fiedler-Weiss 1987). Hair growth response
ranged from sparse regrowth to almost total recovery. However,
other dermatologists report less successful response rates.
Laboratory tests on anthralin have attributed it with a number
of alopecia areata limiting properties:
- It generates free radicals and oxygen radicals.
- It inhibits
the human monocytes from secreting IL-6, IL-8, and tumor necrosis
factor-a but not IL-l.
- It also inhibits the epidermal growth
factor signaling.
While not all of these actions would seem to be beneficial for
hair follicle growth, it seems that the anthralin action has a
much more powerful impact on the inflammatory cells than it does
on the hair follicles. The overall net effect is that anthralin
produces a more favorable environment for hair growth.
In the first-ever attempt to bring about hair-growth in AA patients
by triggering a non-allergic, inflammatory dermatitis, Schmoeckel
and colleagues treated 32 AA patients with Anthralin. Of the 32
patients, about 8 had alopecia totalis and the remaining 24 had
patchy areata (with 6 patients showing ophiasis or band-pattern
alopecia areata). All the patients were treated with 0.2% to 0.8%
anthralin based ointments – applied once regularly on all
alopecia areata-affected areas. Treatment was interrupted when
the dermatitis induced caused
severe itching and blistering. Hair re-growth started somewhere
between 5 to 8 weeks and initially presented as thin, white hairs,
which, afterward became re-pigmented. At least 18 of the 24 patients
with patchy alopecia areata experienced heightened improvement
in the alopecia areata condition. Among the remaining 6, 3 had
transient hair-growth and 3 showed no response to the treatment.
Two of
the 8 alopecia totalis patients
showed more than satisfactory results with the treatment. Two
people had only vellus hair and one had temporary hair growth.
The other three patients did not respond to Anthralin treatment.
Fiedler-Weiss and Buys examined the effectiveness of anthralin
cream in the treatment of 66 alopecia areata patients aged between
4 and 68 years. Drithocreme, a 0.5% Anthralin cream was applied
at bedtime on alternate days (for the first two weeks) and then
regularly for a period of about 28 weeks. Patients were required
to shampoo off with zinc pyrithione eight hours after applying
the Anthralin cream. Some of the patients started responding
to treatment within the first 3 months. About 15 of the 29 patients
(with 75% to 100% scalp hair loss), 16 of 33 patients (with 25%
to 74% scalp hair loss) and the other 4 patients with less than
24% of the scalp hair affected showed some hair re-growth. Ultimately,
44 patients of the 66 treated (about 67%) showed a marked improvement
in the condition (the mean time to respond was 11-weeks). Satisfactory
terminal hair re-growth was seen in 13 of 66 patients.
Those who did not show any improvement in the AA condition even
after undergoing a 0.5% anthralin treatment for 6 months were
then treated with 1% anthralin cream. The exposure time to 1%
anthralin was initially fixed at 30 minutes, which was then increased
depending on the
tolerance of the patient to the cream. The success-rate of 1.0%
anthralin treatment was satisfactory with 17 patients exhibiting
sufficient
terminal
hair re-growth.
A small study conducted by Nelson and Spielvogel addressed the
issue of whether the degree of irritation was linked with the
degree of treatment response. Ten patients with varying
degrees of alopecia areata (1 or 2 cm patches or alopecia totalis)
were treated with anthralin cream (0.1%, 0.25% or 0.5%) or 0.4%
anthralin
lotion once or twice daily. (Usage of the cream / lotion
was restricted to the area affected by alopecia areata). Though
the exact statistical figures were not published, the study indicated
that
the efficacy
of anthralin treatment was directly proportional to the degree
of inflammation.
The studies brought the following treatment side effects to the
fore – erythema, pruritus and scaling. Local pyoderma and
regional lymphadenopathy were detected in patients not following
up with zinc pyrithione shampoo.
Non
specific irritants: nitrogen mustard
Nitrogen mustard, also called mechlorethamine hydrochloride,
seems to be an effective alopecia areata remedy for some patients.
A study involving 11 patients (5 with 25% to 99% scalp hair loss
and 6 with alopecia totalis) is evidential. All the patients (aged
between 16 and 65) were treated with topical nitrogen mustard – an
aqueous solution containing 0.2 mg/mL of mechlorethamine hydrochloride – all
over the scalp daily. This routine was continued until terminal
hair growth was noted. Thereafter, the frequency of applications
was decreased to three times a week and this effected normal hair-growth.
Treatment was continued for 2 more months with the application
frequency being once a week. Following the full-length treatment
with nitrogen mustard, 3 of the localized alopecia patients showed
100 percent re-growth and 2 showed 10 percent re-growth. Of the
6 alopecia totalis patients, 2 had complete re-growth, 1 experienced
about 60 percent re-growth and another patient showed 20 percent
hair
re-growth.
Two alopecia totalis patients developed severe drug reactions
and their treatment was abandoned halfway.
Irritants
for the treatment of alopecia areata references
- Sasmaz S, Arican O. Comparison of azelaic acid
and anthralin for the therapy of patchy alopecia areata: a pilot
study. Am J Clin Dermatol. 2005;6(6):403-6.
PMID: 16343028
- Tang L, Cao L, Sundberg
JP, Lui H, Shapiro J. Restoration
of hair growth in mice with an alopecia areata-like disease
using
topical anthralin. Exp Dermatol. 2004 Jan;13(1):5-10. PMID:
15009110
- Bernardo O, Tang L, Lui H, Shapiro J.
Topical nitrogen mustard in the treatment of alopecia areata:
a bilateral comparison study. J Am Acad Dermatol. 2003 Aug;49(2):291-4.
PMID: 12894080
- Tang L, Cao L, Bernardo O, Chen Y, Sundberg JP, Lui H, Chung
S, Shapiro J. Topical mechlorethamine
restores autoimmune-arrested follicular activity in mice with
an alopecia areata-like disease by targeting infiltrated lymphocytes.
J Invest Dermatol. 2003 Mar;120(3):400-6.
PMID: 12603852
- Tang L, Cao L, Pelech S, Lui H, Shapiro J.
Cytokines and signal transduction
pathways mediated by anthralin in alopecia areata-affected Dundee
experimental
balding rats. J Investig Dermatol Symp Proc. 2003 Jun;8(1):87-90.
PMID: 12895001
- Shapiro
J,
Price VH. Hair
regrowth.
Therapeutic agents. Dermatol Clin. 1998 Apr;16(2):341-56.
PMID: 9589208
- Fiedler VC, Wendrow
A, Szpunar GJ, Metzler C, DeVillez
RL. Treatment-resistant alopecia areata.
Response to
combination therapy with minoxidil plus anthralin.
Arch
Dermatol. 1990 Jun;126(6):756-9. PMID: 2140670
- Fiedler-Weiss
VC, Buys CM.
Evaluation of anthralin
in the treatment of alopecia areata.
Arch Dermatol. 1987 Nov;123(11):1491-3.
PMID: 3314718
- Nelson DA, Spielvogel
RL.
Anthralin therapy for alopecia areata. Int J Dermatol. 1985
Nov;24(9):606-7.
PMID:
3905640
- Arrazola JM, Sendagorta E, Harto A, Ledo A. Treatment of alopecia
areata with topical nitrogen mustard. Int J Dermatol. 1985 Nov;24(9):608-10.
PMID: 4066107
- Schmoeckel C, Weissmann I, Plewig G, Braun-Falco O. Treatment
of alopecia areata by anthralin-induced dermatitis. Arch Dermatol.
1979 Oct;115(10):1254-5.
PMID: 159668
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