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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
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
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/.
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
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.
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
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)
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)
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
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
* * * * * * * ** ** ** ** ** ** **
* * * * * * *
n=3 n=22 n=17 n=4 n=2 n=10 n=10−9.5
−9
−8.5
−8
−7.5
−7
−6.5
−6
Normal Scalp AA AD PsOGroup
log 2(E
xpre
ssio
n/hA
RP )
TissueNormalNLLS
CCL5
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
NormalSkin
log 2(E
xpre
ssio
n/hA
RP)
IFNγ
PsoADAANormalScalp
* * * * * * * *
* * * * * * * * ** ** ** ** ** ** ** **
** ** ** ** ** ** ** **
************************
−14.25
−13
−11.75
−10.5
−9.25
−8
−6.75
log 2(E
xpre
ssio
n/hA
RP )
CXCL9
NormalSkin
PsoADAANormalScalp
************************
************************
* * * * * * * *
** ** ** ** ** ** ** ** ************************
** ** ** ** ** ** ** **
−16.25
−15
−13.75
−12.5
−11.25
−10
−8.75
log 2(E
xpre
ssio
n/hA
RP )
CXCL10
NormalSkin
PsoADAANormalScalp
** ** ** ** ** ** ** **
* * * * * * * *
** ** ** ** ** ** ** **
* * * * * * * *
* * * * * * * *
* * * * * * * *
* * * * * * * *
************************
−24
−22
−20
−18
−16
−14
log 2(E
xpre
ssio
n/hA
RP)
IL−12/IL−23p40
NormalSkin
PsoADAANormalScalp
************************ ** ** ** ** ** ** ** ** * * * * * * * *
************************ ************************
−14
−13.5
−13
−12.5
−12
log 2(E
xpre
ssio
n/hA
RP )
IL-23p19
NormalSkin
PsoADAANormalScalp
************************
** ** ** ** ** ** ** **
************************
************************
−17
−15.75
−14.5
−13.25
−12
−10.75
log 2(E
xpre
ssio
n/hA
RP)
IL-13
NormalSkin
PsoADAANormalScalp
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
PDE axis is also significantly elevated in Alopecia Areata
Lesional
Suarez-Farinas..and Guttman-Yassky E et al. JACI 2015.
Oral apremilast causes hair regrowth in human scalp graVs on mouse models
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
Applying Th2 targeUng strategies that are successful in Eczema for AA: Dupilumab
Pre Dupilumab/anU IL-‐4R Monoclonal anUbody (suppressing the Th2 lymphocyte pathway)
Post Dupilumab treatment
Pre Dupilumab Treatment
E AD Pre (001)
W0
W16
W16
W28
W28
W28
W49
W49
W49
W20
W20
Clinical Improvement (%)
Perc
ent I
mpr
ovem
ent
1 2 3
Patient
A
B
C
D E Immune Genes
Normal.Pre
NL.Pre
LS.Pre
LS.Post
KRTAP7−1 −−−−: −13.30+ −57.70** 6.64+ KRT72 −−−−−−−: −16.70* −3.77 4.74* KRT86 −−−−−−−: −27.50+ −6.59 2.26 KRTAP9−2 −−−−: −20.60+ −5.82 1.55 KRTAP4−6 −−−−: −37.50* −12.00+ 2.45 KRTAP4−9 −−−−: −38.30+ −11.70+ 3.00 KRTAP3−2 −−−−: −35.80* −11.90+ 3.02 KRTAP5−8 −−−−: −150.00** −107.00** 30.40** KRTAP4−8 −−−−: −44.20* −36.80** 7.82* KRTAP8−1 −−−−: −28.50+ −35.20* 6.44 KRT73 −−−−−−−: −14.30+ −5.29+ 5.59+ KRTAP17−1 −−−: −367.00** −99.20** 35.60** KRTAP10−11 −−: −243.00** −60.10** 23.10** KRT33A −−−−−−: −94.90** −28.00** 13.30** KRT82 −−−−−−−: −293.00** −72.60** 38.80** KRT40 −−−−−−−: −83.40** −29.70** 19.30** KRTAP10−12 −−: −26.90** −13.00** 8.80** KRT32 −−−−−−−: −64.10* −18.80* 13.60* KRT74 −−−−−−−: −34.10* −12.90* 8.86* KRT31 −−−−−−−: −32.70** −13.30** 8.48** KRTAP19−1 −−−: −110.00** −54.20** 12.50* KRTAP9−9 −−−−: −53.40* −25.10* 7.97+ KRT27 −−−−−−−: −36.10* −11.50* 7.11* KRT83 −−−−−−−: −365.00** −43.90* 20.90* KRT75 −−−−−−−: −53.30* −14.50* 7.51* KRT33B −−−−−−: −185.00** −33.70* 11.60* KRTAP2−1 −−−−: −130.00** −31.50** 10.70* KRTAP11−1 −−−: −191.00** −42.00* 12.60* KRT16 −−−−−−−: −4.13* −2.92* 2.09* KRT35 −−−−−−−: −153.00* −41.80* 12.50+ KRT85 −−−−−−−: −54.70* −20.60* 7.29+ KRT81 −−−−−−−: −132.00** −21.50* 7.55+ KRT84 −−−−−−−: −17.30** −6.08* 3.00+ KRTAP3−3 −−−−: −77.70* −17.40* 5.07 KRTAP1−5 −−−−: −36.10+ −16.00+ 4.25 KRTAP4−5 −−−−: −177.00** −43.90** 10.90* KRTAP1−3 −−−−: −75.60* −24.00* 6.89+ KRTAP2−3 −−−−: −155.00** −50.80** 11.20* KRTAP4−11 −−−: −64.10* −26.20* 6.30+ KRTAP9−3 −−−−: −42.30* −18.60* 5.13 KRTAP4−4 −−−−: −90.70* −31.40* 7.80+ KRTAP4−3 −−−−: −69.00* −26.70* 6.76+ KRTAP4−1 −−−−: −53.30* −18.90* 4.88 KRTAP4−12 −−−: −81.50* −23.80* 5.84 KRTAP1−1 −−−−: −58.10* −18.80* 4.98 KRTAP3−1 −−−−: −121.00* −30.40* 7.12+ KRT34 −−−−−−−: −54.70* −17.50* 5.39+ KRTAP4−7 −−−−: −49.40* −15.50* 4.49 KRTAP9−4 −−−−: −45.50* −14.10* 4.58 KRTAP9−8 −−−−: −43.20* −13.70+ 4.56
Keratin Genes LS Pre vs Post
−2 −1 0 1 2
Row Z−Score
Color Key
Clinical Improvement (%)
Patient Pe
rcen
t Im
prov
emen
t
Pre LS Post LS NL Normal
Figure 1
W20
W0 W20 W0
W0 W20 W20
Normal.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
Immune Genes (JACI) LS Post vs Pre
−2 0 1 2
Row Z−Score
Color Key
Normal.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
Immune Genes (JACI) LS Post vs Pre
−2 0 1 2
Row Z−Score
Color Key
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
Immune Genes: Baseline
Hair Keratin Genes: Baseline
1 2 3
Patient
1 2 3
Patient
GS
VA
Score!
GS
VA
Score!
C Pathway Change with Treatment
B
A
1 2 3
Patient
Keratin Genes: Baseline
Figure 2
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"
GSVA analysis of response to treatment
Immune Genes: Baseline
Hair Keratin Genes: Baseline
1 2 3
Patient
1 2 3
Patient
GS
VA
Score!
GS
VA
Score!
C Pathway Change with Treatment
B
A
1 2 3
Patient
Keratin Genes: Baseline
Figure 2
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
GSV
A Score
0-‐
4-‐
8-‐
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
Thank You
We are now beginning an exciUng path for a new treatment paradigm for our paUents with alopecia areata
