Different pathways might drive the inflammation in alopecia areata and clinical trials utilizing narrow-targeted therapeutics will be able to elucidate the role of each cytokine pathway in the disease phenotype.

1. Cytokine Targeted Treatments
in AA (and how it can benefit
from research in atopic
dermatitis and psoriasis)
Emma Guttman-Yassky MD PhD
Professor
and
Vice
Chair,
Dermatology
Director,
Laboratory
for
Inflammatory
skin
diseases
Icahn
School
of
Medicine
at
Mount
Sinai
Medical
Center,
NY
Emma.GuDman@mountsinai.org

2. Inflammatory
Pathways
in
Atopic
Derma55s
and
Targeted
treatments
Ustekinumab
Secukinumab
ILV-094
Tezepelumab
GBR 830
Dupilumab
Nemolizumab
BMS-981164
Non-Lesional Acute Chronic
Tralokinumab
Lebrikizumab
JAK
inhibitors
Apremilast
Noda S, Krueger JG, and Guttman-Yassky E.
J Allergy Clin Immunol 2015

3. Alopecia areata
u Lifetime prevalence: 1.7%
u Over 6.6M in the US and 147M worldwide
u Usually affects the scalp, but can also affect other
hairy areas
u ~10% of patients progress to total scalp/Alopecia
Totalis (AT) or body hair loss/ Alopecia Universalis
(AU)
u AA causes tremendous emotional and psychosocial
distress to patients and families
Gilhar A et al. N Engl J Med 2012
Huang KP et al. JAMA Dermatol 2013
https://www.naaf.org/.

4. Alopecia Areata
Multiple treatments exist for AA (with varying efficacy
and many side effects)
Alkhalifah A.
Dermatol Ther 2011.
• Intralesional steroids
– The standard of care for
localized lesions
– Painful
– Causes scalp atrophy
– Limited efficacy
• Other treatments
– DPCP (diphenylcyclopropenone)
– Topical calcineurin inhibitors
– Topical minoxidil
– Topical steroids
– Systemic Treatments(é side effects)
– Systemic steroids
– Cyclosporine A
– Phototherapy: NB UVB, PUVA

5. AA is highly associated with Atopy
Comorbidities of AA:
38.2% Atopy (allergic rhinitis, asthma, and/or eczema)
25.5% Depression or anxiety
24.5% Hyperlipidemia
21.9% Hypertension
17.3% Gastroesophageal reflux disease
14.6% Thyroid disease
11.1% Diabetes mellitus
6.3% Psoriasis and psoriatic arthritis
4.3% Systemic lupus erythematosus
3.9% Rheumatoid arthritis
2.0% Inflammatory bowel disease
Huang KP et al.
JAMA Dermatol 2013
GWAS studies: IL-13, CTLA4, IL-2RA, IL-2/IL-21, ULBP3/ULBP6,
PRDX5,
STX17,
and
IKZF4/ERBB3
idenUfied
in
the
1st
North
American
study
Jagielska
D
et al. J
Invest
Dermatol.
2012
Sep;132(9):2192-­‐7.

6. Previous studies mostly focused on Th1/IFNγ axis
Xing L et al. Nat Med 2014.
• IFN-γ produced by CD8+ T-cells leads to the collapse of immune privilege in the hair
follicle, inducing further production of IL-15 and a feed-forward loop that promotes
type I cellular autoimmunity

7. However,
some
studies
have
shown
increased
Th2
axis
in
AA
paUents
• Increased
expression
of
IL-­‐4,
IL-­‐5,
and
IL-­‐10
in
the
skin
of
AA
paUents
(Barahmani
N
JAAD
2009)
• Increased
IL-­‐5
and
IL-­‐6
in
serum
(Shohat
M
Clin
Exp
Dermatol
2005)
• Elevated
serum
IL-­‐4,
IgE
levels,
and
eosinophilia
in
AA
(Zhang
X
Arch
Dermatol
Res
2015,
Ada
EA
Dermatol
Res
Pract
2010,
Kasumagic-­‐Halilovic
E
Acta
Dermatovenerol
Croat
2006)
• FLG
mutaUons
significantly
associated
with
more
severe
clinical
presentaUon
of
AA
paUents
with
AD
(Betz
RC
J
Invest
Dermatol
2007)
• Recent
publicaUons
highlighted
a
Th2
gene
signature:
5
of
6
transcripUonal
AA
blood
and
skin
genomic
“hot
spots”
coincided
with
regions
previously
reported
as
relevant
to
AD
suscepUbility
(Coda
AS
Genomics
2011,
Coda
AB
Genes
and
Immunity
2010,
Subramanya
ED
Genomics
2010
)
• Greatest
risk
factor
for
AA
is
AD
(Barahmani
N
JAAD
2009)

8. Treatment
of
alopecia
areata
with
tofaci'nib
5mg
twice
daily
results
in
hair
regrowth
JAK
Inhibitors
(in
Open
Label
Trials)
are
Effec5ve
for
Hair
Regrowth)

9. Because of broad inhibition of multiple cytokines and
pathways, JAK inhibitors cannot tease out the
pathogenesis of AA
Via
JAK3,
tofaciUnib
inhibits
cytokines
with
γ
chain
signaling
include
IL-­‐2,
IL-­‐4,
IL-­‐7,
IL-­‐15,
IL-­‐21
RuxoliUnib
inhibits
JAK2
and
both
inhibit
JAK1,
so
there
is
inhibiUon
of
IFNγ,
IL-­‐6,
IL-­‐10,
IL-­‐12,
IL-­‐22

10. This prompted us to perform a large study to profile
inflammatory cytokines and pathways in AA
First
extensive
genomic
profiling
of
AA
in
large
cohort
(N=27
pts)
27
lesional
scalp
samples
17
non-­‐lesional
scalp
samples
5
normal
scalp
samples
from
published
data
(GSE45512)
Suarez-Farinas..and Guttman-Yassky E et al. JACI 2015.
Increased
expression
of
immune
genes
in
LS
scalp
Decreased
expression
of
keraUn
genes
in
LS
scalp

11. Tissue
Normal
NL
LS
AA is Characterized By Th1, Th2, and IL-23 activation
Mayte
Suarez-­‐Farinas…and
GuHman-­‐Yassky
E.
JACI
August
2015
Th1
IL-­‐23
Th2
********
****************
********
****************************************
************************
−18
−17
−16
−15
−14
−13
−12
Normal
Skin
log2(Expression/hARP)
IFNγ
PsoADAANormal
Scalp
********
********
****************
****************
************************
−14.25
−13
−11.75
−10.5
−9.25
−8
−6.75
log2(Expression/hARP)
CXCL9
Normal
Skin
PsoADAANormal
Scalp
************************
************************
********
****************
************************
****************
−16.25
−15
−13.75
−12.5
−11.25
−10
−8.75
log2(Expression/hARP)
CXCL10
Normal
Skin
PsoADAANormal
Scalp
****************
********
****************
********
********
********
********
************************
−24
−22
−20
−18
−16
−14
log2(Expression/hARP)
IL−12/IL−23p40
Normal
Skin
PsoADAANormal
Scalp
************************
****************
********
************************
************************
−14
−13.5
−13
−12.5
−12
log2(Expression/hARP)
IL-23p19
Normal
Skin
PsoADAANormal
Scalp
************************
****************
************************
************************
−17
−15.75
−14.5
−13.25
−12
−10.75
log2(Expression/hARP)
IL-13
Normal
Skin
PsoADAANormal
Scalp
N
Scalp
AA
AD
PSO
N
Skin
N
Scalp
AA
AD
PSO
N
Skin
N
Scalp
AA
AD
PSO
N
Skin
N
Scalp
AA
AD
PSO
N
Skin
IFNγ
CXCL9
CXCL10
IL-­‐23p19
IL-­‐12/23p40
IL-­‐13
N
Scalp
AA
AD
PSO
N
Skin
N
Scalp
AA
AD
PSO
N
Skin

12. PDE
axis
is
also
significantly
elevated
in
Alopecia
Areata
Lesional
Suarez-Farinas..and Guttman-Yassky E et al. JACI 2015.

13. Oral
apremilast
causes
hair
regrowth
in
human
scalp
graVs
on
mouse
models

14. u AA
might
present
a
similar
model
to
atopic
dermaUUs
in
which
immune
cytokines
suppress
formaUon
of
hair
keraUns
u Specific
cytokine
inhibiUon
is
needed
to
dissect
the
mechanisms
underlying
AA
u At
Icahn
School
of
Medicine
at
Mount
Sinai
we
offer
the
largest
available
clinical
trials
for
AA
paUents
targeUng
different
pathways
u We
offer
several
broad
and
specific
targeted
treatments
for
AA
inhibiUng
(PDE4/Apremilast,
JAK,
the
Th2
pathways,
anU
IL-­‐12/23p40
and
more
to
come
this
year)—majority
as
single
center
(or
two
center
trials)
How
are
we
applying
this
new
knowledge
to
novel
therapeuUcs
for
AA

15. Applying
Th2
targeUng
strategies
that
are
successful
in
Eczema
for
AA:
Dupilumab
Pre
Dupilumab/anU
IL-­‐4R
Monoclonal
anUbody
(suppressing
the
Th2
lymphocyte
pathway)

17. Post Dupilumab
treatment
Pre
Dupilumab
Treatment

18. E AD Pre (001)
W0
W16
W16
W28
W28
W28
W49
W49
W49
W20
W20
Clinical Improvement (%)
PercentImprovement
1 2 3
Patient
A
B
C
D E Immune Genes
Normal.Pre
NL.Pre
LS.Pre
Keratin Genes LS Pre vs
−2 −1 0 1 2
Row Z−Score
Color Key
Clinical Improvement (%)
Patient
PercentImprovement
Pre LS Post LSNLNormal
Figure 1
W20
W0 W20W0
W0 W20W20
mal.Pre
NL.Pre
LS.Pre
LS.Post
CD3D −−−−: 1.64 1.52 −1.65
CD4 −−−−−: 1.64 1.52 −1.55+
PDE4A −−−: 1.80+ 1.83* −2.03**
IL32 −−−−: 1.35 1.40 −1.50
PDE1A −−−: 1.34 1.63 −2.54**
STAT3 −−−: −1.07 −1.15 1.23+
CD3G −−−−: 1.32 1.20 −1.77
IFNGR1 −−: −1.03 −1.01 1.10
CCR7 −−−−: 1.62 1.46 −1.04
CCL18 −−−: 28.90** 6.11** −1.46
JAK2 −−−−: 1.57 1.93* −1.17
CCL26 −−−: 7.36* 7.83** −2.17
CD1B −−−−: 5.98* 6.46** −1.86
MMP12 −−−: 3.14 5.13+ −2.55
IL15 −−−−: 1.77 1.63 −1.49
S100P −−−: −2.13** −2.08** 1.71**
IL33 −−−−: 1.22 −1.11 1.11
CXCL9 −−−: 15.30* −1.49 1.57
IL7 −−−−−: 3.00** 1.09 1.16
AHR −−−−−: 1.69* 1.02 1.08
CXCL10 −−: 8.10 −1.37 −1.40
TSLP −−−−: 1.91 1.05 −1.42
CD28 −−−−: 5.14 −1.46 −2.37
LCK −−−−−: 1.46 1.29 −1.24
IRF1 −−−−: 2.25+ 1.58 −1.43
CCL13 −−−: 9.62** 3.16* −2.94*
CCL2 −−−−: 3.45* 1.24 −1.36
JAK1 −−−−: 1.88+ 1.28 −1.22
ITGAX −−−: 1.84 1.27 −1.38
STAT1 −−−: 4.82** 1.76+ −1.90*
CD86 −−−−: 4.61* 1.63 −1.88+
CCL5 −−−−: 2.70 1.84 −2.20
CCR2 −−−−: 2.34 1.57 −2.02+
PDE4B −−−: 2.73* 1.55 −2.36**
CD69 −−−−: 1.56 1.09 −1.52
JAK3 −−−−: 2.12 1.18 −1.89
ITGB2 −−−: 2.66 1.44 −2.44*
CD2 −−−−−: 1.66 1.19 −1.62
PDE3A −−−: 3.54** 1.28 −2.37**
CD83 −−−−: 1.72 1.19 −1.44
IL23A −−−: 1.67 1.21 −1.46
−2 0 1 2
Row Z−Score
rmal.Pre
NL.Pre
LS.Pre
LS.Post
CD3D −−−−: 1.64 1.52 −1.65
CD4 −−−−−: 1.64 1.52 −1.55+
PDE4A −−−: 1.80+ 1.83* −2.03**
IL32 −−−−: 1.35 1.40 −1.50
PDE1A −−−: 1.34 1.63 −2.54**
STAT3 −−−: −1.07 −1.15 1.23+
CD3G −−−−: 1.32 1.20 −1.77
IFNGR1 −−: −1.03 −1.01 1.10
CCR7 −−−−: 1.62 1.46 −1.04
CCL18 −−−: 28.90** 6.11** −1.46
JAK2 −−−−: 1.57 1.93* −1.17
CCL26 −−−: 7.36* 7.83** −2.17
CD1B −−−−: 5.98* 6.46** −1.86
MMP12 −−−: 3.14 5.13+ −2.55
IL15 −−−−: 1.77 1.63 −1.49
S100P −−−: −2.13** −2.08** 1.71**
IL33 −−−−: 1.22 −1.11 1.11
CXCL9 −−−: 15.30* −1.49 1.57
IL7 −−−−−: 3.00** 1.09 1.16
AHR −−−−−: 1.69* 1.02 1.08
CXCL10 −−: 8.10 −1.37 −1.40
TSLP −−−−: 1.91 1.05 −1.42
CD28 −−−−: 5.14 −1.46 −2.37
LCK −−−−−: 1.46 1.29 −1.24
IRF1 −−−−: 2.25+ 1.58 −1.43
CCL13 −−−: 9.62** 3.16* −2.94*
CCL2 −−−−: 3.45* 1.24 −1.36
JAK1 −−−−: 1.88+ 1.28 −1.22
ITGAX −−−: 1.84 1.27 −1.38
STAT1 −−−: 4.82** 1.76+ −1.90*
CD86 −−−−: 4.61* 1.63 −1.88+
CCL5 −−−−: 2.70 1.84 −2.20
CCR2 −−−−: 2.34 1.57 −2.02+
PDE4B −−−: 2.73* 1.55 −2.36**
CD69 −−−−: 1.56 1.09 −1.52
JAK3 −−−−: 2.12 1.18 −1.89
ITGB2 −−−: 2.66 1.44 −2.44*
CD2 −−−−−: 1.66 1.19 −1.62
PDE3A −−−: 3.54** 1.28 −2.37**
CD83 −−−−: 1.72 1.19 −1.44
IL23A −−−: 1.67 1.21 −1.46
−2 0 1 2
Row Z−Score
Pre LS
vs N
Pre LS
vs NL
Post LS
vs Pre LS
GuHman-­‐Yassky
E….Lebwohl
MG,
JACI
December
2015.
Ustekinumab (anti IL-23) causes significant hair growth in 3 AA
patients

19. Immune Genes: Baseline
Hair Keratin Genes: Baseline
1 2 3
Patient
1 2 3
Patient
GSVAScore!
B
A
Keratin Genes: Baseline
Figure 2
GSVA
analysis
of
response
to
treatment
C Pathway Change with Treatment
AA LS vs. NL "
Transcriptome (Up)"
Immune Genes"
ALADIN KER Score"
Th2 Score"
ALADIN IFN Score"
ALADIN CTL Score"
PDE Score"
Th1 Super-enhancers"
Th2 Super-enhancers"
IL-12/23 Score"
-­‐ PaUents
2
and
3
followed
a
similar
paDern
-­‐ PaUents
2
and
3
had
more
inflammaUon
at
baseline
With
treatment,
there
was
a
reducUon
in:
-­‐ All
PaUents
had
an
increase
in
ALADIN
KER
Score
-­‐ The
AA
LS
vs.
NL
transcriptome
(Suarez-­‐Farinas
et
al.
JACI
2015)
-­‐ Immune
genes
-­‐ IL-­‐12/23
induced
genes
-­‐ ALADIN
IFN
and
CTL
scores
-­‐ Th2
score
-­‐ Th1
and
Th2
Super-­‐enhancers
-­‐ PDE
score
Pathway
Change
with
Treatment
GSVA
Pathway
Scores
AA
LS
vs.
NL
Transcriptome
(Up)
Immune
Genes
IL-­‐12/23
Score
ALADIN
IFN
Score
ALADIN
CTL
Score
ALADIN
KER
Score
Th2
Score
PDE
Score
Th1
Super-­‐enhancers
Th2
Super-­‐enhancers
1
3
Pa5ent
2
Immune
Genes:
Baseline
Pa5ent
1
2
3
GSVA
Score
0-­‐
4-­‐
8-­‐

20. Conclusions
u This is the first preliminary report of extensive AA patients
that demonstrate significant hair re-growth with specific
cytokine antagonism
u Higher inflammation at baseline was associated with
better clinical responses
u In addition to expected Th1 inhibition, significant
modulation of Th2, IL-23 and PDE genes were also seen
u In addition to previously published AA-specific scores
(ALADIN IFN, CTL and KER) it is important to follow
modulation of Th2 and PDE genes
u Trials with larger cohorts are necessary to evaluate
IL-12/23 and other cytokine inhibition

21. Thank
You
We
are
now
beginning
an
exciUng
path
for
a
new
treatment
paradigm
for
our
paUents
with
alopecia
areata
Emma.GuDman@mountsinai.org