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Dermatologic Therapy, Vol. 24, 2011, 364–368
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© 2011 Wiley Periodicals, Inc.
DERMATOLOGIC THERAPY
ISSN 1396-0296
Treatment of alopecia areata:
“What is new on the horizon?”
dth_1421
364..368
Maria K. Hordinsky
Department of Dermatology, University of Minnesota, Minneapolis,
Minnesota
ABSTRACT: New drug treatment opportunities based on the results of a genome-wide association
study, which implicate T cell and natural killer (NK)-cell activation pathways, are leading to new
approaches in future clinical trials of alopecia areata. Special attention is being given to the UL
16-binding protein (ULBP3) gene cluster on chromosome 6q25, as these genes make the NKG2Dactivating ligand or signal that can trigger the NKG2D receptor, initiating an autoimmune response. A
greater expression of ULBP3 has also been found in hair follicles in scalp biopsy specimens from
patients with active disease. It is now postulated that the characteristic T cell “swarm of bees” infiltrate
seen in alopecia areata is the result of T cells being attracted to the hair follicle by NKG2D-activating
ligands. Future treatment approaches for alopecia areata include use of drugs that: (i) block the NKGDactivating ligand and NKG2D receptor interaction, (ii) halt activated T cells, or (iii) modification of the
inflammatory cytokine network. Many drugs currently being used or being evaluated for other autoimmune diseases that work through these mechanisms might prove to be very effective in alopecia areata.
KEYWORDS: alopecia areata, clinical trials, genome-wide association study (GWAS)
Introduction
Alopecia areata is a complex genetic, immunemediated disease that targets anagen hair follicles
(1). Characterized by round or oval patches of hair
loss, loss of all scalp hair (alopecia totalis), loss of all
body hair (alopecia universalis), or ophiasis pattern
hair loss, alopecia areata is a relatively common
autoimmune disease that affects both males and
females of all ages and races in all parts of the world.
The lifetime risk for alopecia areata in the United
States is estimated to be approximately 2% (2).
Unfortunately, there is currently no cure for this
chronic disease and, although many therapies are
available, there is no universally proven therapy
that induces and sustains remission (3). In the
United States, there is no FDA-approved therapy
for the treatment of alopecia areata, so treatments
Address correspondence and reprint requests to: Maria K.
Hordinsky, MD, Professor and Chair, Department of
Dermatology, University of Minnesota, Minneapolis, MN
55455, or email: [email protected].
364
are considered “off label.” Current treatment
choices are frequently based on disease extent and
duration, as well as the age of the patient. Treatments include a variety of topical, intralesional,
and systemic agents (1,4).
Pathophysiology
A histopathologic hallmark of alopecia areata is
the presence of perifollicular inflammation and in
particular, a peribulbar infiltrate of predominantly
lymphocytes around anagen follicles (5). This infiltrate is commonly referred to as a “swarm of bees”
and is typically seen in patients with active disease
(FIG. 1). When alopecia areata is more chronic this
infiltrate may not be a striking feature, rather a shift
to the telogen stage of the hair cycle or follicles in
early anagen predominates (FIG. 2). Transplantation studies using severe-combined immunodeficient mice have established that alopecia areata is
transferrable with T cells (6). There is also evidence
to suggest that immune privilege is lost in alopecia
areata (7,8).
Treatment of alopecia areata
FIG. 1. “Swarm of bees” around an anagen hair follicle in a
scalp biopsy taken from a patient with alopecia areata.
treatment of choice for many dermatologists and
in uncontrolled studies variable rates of response
have been found (1,4,9).
Second-line therapies for alopecia areata
include topical minoxidil, anthralin, and phototherapy with psoralen plus near ultraviolet light
(UVA) therapy. Additional second-line therapies
include systemic treatment with oral glucocorticoids, sulfasalazine, cyclosporine, methotrexate, or
combination therapy (1,4,9).
Other therapies that have shown some efficacy
include the excimer laser, topical bexarotene, photodynamic therapy, prostaglandin analogs, and
even fractional photothermylysis (1,4,9). Aromatherapy, a natural treatment option, has also been
reported to be effective in some patients (10).
Although there are isolated case reports of different biologics being effective in the treatment of
alopecia areata, attempts to treat this disease with
biologic agents that directly or indirectly alter T cell
function have not proven to be successful in clinical trials. In studies examining: (i) alefacept, a
fusion protein that binds to CD2 and inhibits T cell
activation, (ii) etanercept, a tumor necrosis factoralpha inhibitor, or (iii) efalizumab, a recombinant
humanized monoclonal antibody against CD11a,
none has been shown to be effective in clinical
trials. Of note, the manufacture of efalizumab has
since been discontinued. Moreover, alopecia
areata has been described to develop in patients
while on therapy with adalimumab, infliximab, or
etanercept for other autoimmune disorders (1,4,9).
What is new on the horizon?
FIG. 2. Shift to telogen and miniaturized follicles in a scalp
biopsy taken from a patient with a several-year history of
extensive alopecia areata. The inflammatory infiltrate is still
present, but is not as prominent as seen in patients with acute,
active disease.
Current treatments (1,4,9)
First-line therapies of alopecia areata commonly
include intralesional or topical corticosteroids, and
in some institutions, topical immunotherapy.
There are no randomized trials of intralesional corticosteroids for alopecia areata; however, there are
several published studies investigating the efficacy
of topical corticosteroids in the treatment of this
disease. Topical immunotherapy, the preferred
In August 2009, scientists and clinicians with an
interest in alopecia areata and major autoimmunity experts met in Denver, Colorado at a meeting
sponsored by the National Alopecia Areata Foundation. The major goal of this one-day meeting was
to develop future research directions and opportunities for alopecia areata. There were four major
outcomes from this meeting, one being the identification of new potential therapies. The other three
outcomes focused on the determination of key
areas for future research, formation of research
teams to immediately address key gaps in the
knowledge of immune mechanisms in alopecia
areata, and the development of funding strategies
to engage the hair research and autoimmunity
world in alopecia areata research.
At the end of the meeting, a group of investigators
interested in clinical trials/clinical research was
created. The charge given to this group was to
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Hordinsky
review and develop clinical trials using devices as
well as off-the-shelf treatments found to be effective
in other autoimmune diseases. Those devices and
treatments were chosen based on the knowledge of
the immunology and genetics of alopecia areata.
A comprehensive review of all FDA-approved
drugs as well as those in clinical trials for autoimmune diseases was undertaken. Over 230 drugs
were identified, and information was obtained on
generic drug name, trade names, indications,
mechanism, manufacturer (drug company), study
phase, and information as to whether or not the
drug was FDA-approved. Concurrently, a date was
set for a Clinical Research/Translational Summit
on Alopecia Areata. This took place October 23,
2010 at Columbia University in New York City and
brought together leaders in alopecia areata clinical
research, as well as those in drug delivery, immunology drug development, and experts from the
National Institutes of Health. The discussions at
the Summit focused on several subjects including
those summarized in Table 1. Incorporated into
the discussion of the Summit were the results of the
recently published genome-wide association study
(GWAS) and discussion of new drug treatment
opportunities based on the results of these studies,
in which T cells and natural killer (NK)-cell activation pathways were implicated (11). The stage was
set for not only new approaches in clinical trials,
but also plans for developing a translational platform with biomarkers.
Key findings from the GWAS (12)
Key genes that were found in the GWAS studies are
summarized in Table 2 and include T cell related
genes such as IL2/IL21 (T-, B-, and NK cell proliferation), IL2RA (T cell proliferation), CTLA4 (T cell
proliferation), IKZF4 (T cell proliferation) and HLA
(antigen proliferation), and genes in the hair follicle
including NK-activating ligands ULBP3 and ULBP6,
as well as two other hair follicle genes, STX17 and
peroxiredoxin V (PRDX5). A major new finding was
the identification of cytomegalovirus UL16-binding
protein (ULBP3) gene cluster on chromosome
6q25.1. STX17 encodes a member of the syntaxin
family; syntaxins are involved in vesicle transport.
PRDX5 is an intracellular antioxidant enzyme (11).
The importance of the ULBP genes is that they
make the NKG2D-activating ligand or signal that
can trigger the NKG2D receptor, which, in turn, can
initiate a response and more NKG2D-activating
ligands or signals providing an opportunity to
trigger autoimmunity. This is now postulated to be
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Table 1. Alopecia areata clinical research summit
– summary of subjects covered
1. Need for safe and effective treatments for alopecia
areata
2. Definition of quality of life issues
3. Review of what worked and what did not work in
past clinical studies of alopecia areata
4. Insights into immune targets for alopecia areata
5. New treatment opportunities based on drugs being
developed for other autoimmune diseases
6. New treatment opportunities for devices for alopecia
areata patients
7. Review of different drug delivery methods
8. Standardization of all future alopecia areata clinical
trials in organization, selection of patients, and
regrowth measurement
Table 2. Summary of genes implicated in alopecia
areata from the GWAS studies
1. Immune system
• T cell related genes
IL2/IL21, IL2RA, CTLA4, IKZF4, HLA
2. In the hair follicle
• NK-activating ligands
ULBP3, ULBP6
• Other hair follicle genes
STX17, PRDX5
a possible mechanism for alopecia areata as well as
other autoimmune diseases. Subsequent immunohistochemical studies on affected alopecia areata
scalp, as well as normal scalp, have found higher
levels of ULBP3 expressed in the hair follicles of
patients with an active disease.
This new information has been integrated to
suggest that alopecia areata is related to the
“swarm of bees” that has characterized this disease
for decades. However, the bees have now been
identified as killer CD8 cells, which are attracted to
the hair follicle by the NKG2D-activating ligand.
These findings have opened new avenues of exploration for therapies based on the underlying
mechanisms of alopecia areata, permitting treatments to be developed on what we have known,
including mechanisms common to other types of
autoimmunity and T cell related mechanisms that
involve signaling pathways downstream of the
NKG2D receptor (5,11).
New trends
Proposed treatment approaches to alopecia areata
now fall into three broad categories and can
Treatment of alopecia areata
Table 3. Potential therapies to test in clinical trials
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Anti-CD25
Anti-CTLA-4
Jak 1/2 inhibitor
Anti-NKG2D
Syk inhibitor
Anti-IL-15
Anti-IL-6
Anti-IFNg
Anti-TAP2
Anti-IL-1
Anti-IL-17
Anti-PDE4
include drugs already being used effectively in
many autoimmune diseases. The three approaches
could do any of the following:
1. Block NK cell innate immunity
2. Halt activated T cells
3. Modify the inflammatory cytokine network
Approaches discussed at the Summit included
blocking the innate/NKG2D response (UBLP3,
UBLP6, and MICA) and/or antigen presenting
cells/sentinel (HLA, TAP, and IFN-g) targeting
adaptive immunity such as IL-15, which drives the
NKG2D axis and itself could be a good target or the
use of Jak inhibitors, which might block TH1 cytokines that are postulated to drive alopecia areata
(12–14).
There are multiple drugs currently being evaluated for other autoimmune diseases that could
potentially be very effective in alopecia areata
providing new treatment opportunities. For drugs
that are not yet FDA-approved, the consensus
from the Summit was that the selection and study
of drugs in Phase III of development would be
most practical.
From the discussions at the Summit and after
careful review of approximately 238 drugs in different phases of development or already approved by
the FDA in the United States for the treatment of
autoimmune diseases, a short list of potential systemic or topical choices to study in alopecia areata
was generated. Most of these are antibodies or peptides that block specific immune functions and are
summarized in Table 3.
Summary: the alopecia areata
treatment development program
In September 2000, the National Institute of Arthritis, Metabolism and Skin Diseases funded a 10-year
Alopecia Areata Registry project with a continuation phase through September 2011. The primary
goals of the Registry have been to collect epidemiology data and DNA samples from alopecia areata
patients for the purpose of immunogenetic
research (15).
As of the first quarter of 2011, there were almost
8000 patients and controls who had completed an
online registration for first tier information and
who agreed to be contacted for possible future
clinical trials. There are also greater than 3000
serum and DNA samples from patients who have
been carefully characterized by phenotype, disease
duration, and treatments. These samples come
from patients who participated in the second tier of
the Registry and who were either seen by their dermatologists or in most cases, at one of five study
sites – MD Anderson, Columbia University or the
Universities of California, San Francisco, Colorado,
or Minnesota. Upon completion of the project in
September 2011, the Registry could potentially
expand to a Clinical Trials Network. It is this population of patients as well as patients in clinical practices who will be recruited for the clinical trials and
testing of selected new treatments based on the
immunology and genetics of alopecia areata. The
results of such clinical research studies should
define more effective therapies and longer lasting
remissions in pediatric and adult patients affected
with alopecia areata.
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