Scalp and serum profiling of frontal fibrosing alopecia reveals scalp immune and fibrosis dysregulation with no systemic involvement

Celina Dubin; Jacob W. Glickman; Ester Del Duca; Sumanth Chennareddy; Joseph Han; Dante Dahabreh; Yeriel D. Estrada; Ning Zhang; Grace W. Kimmel; Giselle Singer; Mashkura Chowdhury; Andrew Y. Zheng; Michael Angelov; Jesús Gay-Mimbrera; Juan Ruano Ruiz; James G. Krueger; Ana B. Pavel; Emma Guttman-Yassky

doi:10.1016/j.jaad.2021.05.016

Scalp and serum profiling of frontal fibrosing alopecia reveals scalp immune and fibrosis dysregulation with no systemic involvement

Celina Dubin, Jacob W. Glickman, Ester Del Duca, Sumanth Chennareddy, Joseph Han, Dante Dahabreh, Yeriel D. Estrada, Ning Zhang, Grace W. Kimmel, Giselle Singer, Mashkura Chowdhury, Andrew Y. Zheng, Michael Angelov, Jesús Gay-Mimbrera, Juan Ruano Ruiz, James G. Krueger, Ana B. Pavel, Emma Guttman-Yassky

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Abstract

Background: Frontal fibrosing alopecia (FFA) is a progressive, scarring alopecia of the frontotemporal scalp that poses a substantial burden on quality of life. Large-scale global profiling of FFA is lacking, preventing the development of effective therapeutics. Objective: To characterize FFA compared to normal and alopecia areata using broad molecular profiling and to identify biomarkers linked to disease severity. Methods: This cross-sectional study assessed 33,118 genes in scalp using RNA sequencing and 350 proteins in serum using OLINK high-throughput proteomics. Disease biomarkers were also correlated with clinical severity and a fibrosis gene set. Results: Genes differentially expressed in lesional FFA included markers related to Th1 (IFNγ/CXCL9/CXCL10), T-cell activation (CD2/CD3/CCL19/ICOS), fibrosis (CXCR3/FGF14/FGF22/VIM/FN1), T-regulatory (FOXP3/TGFB1/TGFB3), and Janus kinase/JAK (JAK3/STAT1/STAT4) (Fold changes [FCH]>1.5, FDR<.05 for all). Only one protein, ADM, was differentially expressed in FFA serum compared to normal (FCH>1.3, FDR<.05). Significant correlations were found between scalp biomarkers (IL-36RN/IL-25) and FFA severity, as well as between JAK/STAT and fibrosis gene-sets (r>.6; P <.05). Limitations: This study was limited by a small sample size and predominantly female FFA patients. Conclusion: Our data characterize FFA as an inflammatory condition limited to scalp, involving Th1/JAK skewing, with associated fibrosis and elevated T-regulatory markers, suggesting the potential for disease reversibility with JAK/STAT inhibition.

Original language	English
Pages (from-to)	551-562
Number of pages	12
Journal	Journal of the American Academy of Dermatology
Volume	86
Issue number	3
DOIs	https://doi.org/10.1016/j.jaad.2021.05.016
State	Published - Mar 2022

Keywords

JAK/STAT
OLINK
Th1
alopecia areata
biomarkers
frontal fibrosing alopecia
hair keratins
proteomics

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10.1016/j.jaad.2021.05.016

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Dubin, C., Glickman, J. W., Del Duca, E., Chennareddy, S., Han, J., Dahabreh, D., Estrada, Y. D., Zhang, N., Kimmel, G. W., Singer, G., Chowdhury, M., Zheng, A. Y., Angelov, M., Gay-Mimbrera, J., Ruano Ruiz, J., Krueger, J. G., Pavel, A. B., & Guttman-Yassky, E. (2022). Scalp and serum profiling of frontal fibrosing alopecia reveals scalp immune and fibrosis dysregulation with no systemic involvement. Journal of the American Academy of Dermatology, 86(3), 551-562. https://doi.org/10.1016/j.jaad.2021.05.016

@article{4baf59fdc86b41519c3196eb907dc736,

title = "Scalp and serum profiling of frontal fibrosing alopecia reveals scalp immune and fibrosis dysregulation with no systemic involvement",

abstract = "Background: Frontal fibrosing alopecia (FFA) is a progressive, scarring alopecia of the frontotemporal scalp that poses a substantial burden on quality of life. Large-scale global profiling of FFA is lacking, preventing the development of effective therapeutics. Objective: To characterize FFA compared to normal and alopecia areata using broad molecular profiling and to identify biomarkers linked to disease severity. Methods: This cross-sectional study assessed 33,118 genes in scalp using RNA sequencing and 350 proteins in serum using OLINK high-throughput proteomics. Disease biomarkers were also correlated with clinical severity and a fibrosis gene set. Results: Genes differentially expressed in lesional FFA included markers related to Th1 (IFNγ/CXCL9/CXCL10), T-cell activation (CD2/CD3/CCL19/ICOS), fibrosis (CXCR3/FGF14/FGF22/VIM/FN1), T-regulatory (FOXP3/TGFB1/TGFB3), and Janus kinase/JAK (JAK3/STAT1/STAT4) (Fold changes [FCH]>1.5, FDR<.05 for all). Only one protein, ADM, was differentially expressed in FFA serum compared to normal (FCH>1.3, FDR<.05). Significant correlations were found between scalp biomarkers (IL-36RN/IL-25) and FFA severity, as well as between JAK/STAT and fibrosis gene-sets (r>.6; P <.05). Limitations: This study was limited by a small sample size and predominantly female FFA patients. Conclusion: Our data characterize FFA as an inflammatory condition limited to scalp, involving Th1/JAK skewing, with associated fibrosis and elevated T-regulatory markers, suggesting the potential for disease reversibility with JAK/STAT inhibition.",

keywords = "JAK/STAT, OLINK, Th1, alopecia areata, biomarkers, frontal fibrosing alopecia, hair keratins, proteomics",

author = "Celina Dubin and Glickman, {Jacob W.} and {Del Duca}, Ester and Sumanth Chennareddy and Joseph Han and Dante Dahabreh and Estrada, {Yeriel D.} and Ning Zhang and Kimmel, {Grace W.} and Giselle Singer and Mashkura Chowdhury and Zheng, {Andrew Y.} and Michael Angelov and Jes{\'u}s Gay-Mimbrera and {Ruano Ruiz}, Juan and Krueger, {James G.} and Pavel, {Ana B.} and Emma Guttman-Yassky",

note = "Publisher Copyright: {\textcopyright} 2021 American Academy of Dermatology, Inc.",

year = "2022",

month = mar,

doi = "10.1016/j.jaad.2021.05.016",

language = "English",

volume = "86",

pages = "551--562",

journal = "Journal of the American Academy of Dermatology",

issn = "0190-9622",

publisher = "Elsevier Inc.",

number = "3",

}

Dubin, C, Glickman, JW, Del Duca, E, Chennareddy, S, Han, J, Dahabreh, D, Estrada, YD, Zhang, N, Kimmel, GW, Singer, G, Chowdhury, M, Zheng, AY, Angelov, M, Gay-Mimbrera, J, Ruano Ruiz, J, Krueger, JG, Pavel, AB & Guttman-Yassky, E 2022, 'Scalp and serum profiling of frontal fibrosing alopecia reveals scalp immune and fibrosis dysregulation with no systemic involvement', Journal of the American Academy of Dermatology, vol. 86, no. 3, pp. 551-562. https://doi.org/10.1016/j.jaad.2021.05.016

TY - JOUR

T1 - Scalp and serum profiling of frontal fibrosing alopecia reveals scalp immune and fibrosis dysregulation with no systemic involvement

AU - Dubin, Celina

AU - Glickman, Jacob W.

AU - Del Duca, Ester

AU - Chennareddy, Sumanth

AU - Han, Joseph

AU - Dahabreh, Dante

AU - Estrada, Yeriel D.

AU - Zhang, Ning

AU - Kimmel, Grace W.

AU - Singer, Giselle

AU - Chowdhury, Mashkura

AU - Zheng, Andrew Y.

AU - Angelov, Michael

AU - Gay-Mimbrera, Jesús

AU - Ruano Ruiz, Juan

AU - Krueger, James G.

AU - Pavel, Ana B.

AU - Guttman-Yassky, Emma

PY - 2022/3

Y1 - 2022/3

N2 - Background: Frontal fibrosing alopecia (FFA) is a progressive, scarring alopecia of the frontotemporal scalp that poses a substantial burden on quality of life. Large-scale global profiling of FFA is lacking, preventing the development of effective therapeutics. Objective: To characterize FFA compared to normal and alopecia areata using broad molecular profiling and to identify biomarkers linked to disease severity. Methods: This cross-sectional study assessed 33,118 genes in scalp using RNA sequencing and 350 proteins in serum using OLINK high-throughput proteomics. Disease biomarkers were also correlated with clinical severity and a fibrosis gene set. Results: Genes differentially expressed in lesional FFA included markers related to Th1 (IFNγ/CXCL9/CXCL10), T-cell activation (CD2/CD3/CCL19/ICOS), fibrosis (CXCR3/FGF14/FGF22/VIM/FN1), T-regulatory (FOXP3/TGFB1/TGFB3), and Janus kinase/JAK (JAK3/STAT1/STAT4) (Fold changes [FCH]>1.5, FDR<.05 for all). Only one protein, ADM, was differentially expressed in FFA serum compared to normal (FCH>1.3, FDR<.05). Significant correlations were found between scalp biomarkers (IL-36RN/IL-25) and FFA severity, as well as between JAK/STAT and fibrosis gene-sets (r>.6; P <.05). Limitations: This study was limited by a small sample size and predominantly female FFA patients. Conclusion: Our data characterize FFA as an inflammatory condition limited to scalp, involving Th1/JAK skewing, with associated fibrosis and elevated T-regulatory markers, suggesting the potential for disease reversibility with JAK/STAT inhibition.

AB - Background: Frontal fibrosing alopecia (FFA) is a progressive, scarring alopecia of the frontotemporal scalp that poses a substantial burden on quality of life. Large-scale global profiling of FFA is lacking, preventing the development of effective therapeutics. Objective: To characterize FFA compared to normal and alopecia areata using broad molecular profiling and to identify biomarkers linked to disease severity. Methods: This cross-sectional study assessed 33,118 genes in scalp using RNA sequencing and 350 proteins in serum using OLINK high-throughput proteomics. Disease biomarkers were also correlated with clinical severity and a fibrosis gene set. Results: Genes differentially expressed in lesional FFA included markers related to Th1 (IFNγ/CXCL9/CXCL10), T-cell activation (CD2/CD3/CCL19/ICOS), fibrosis (CXCR3/FGF14/FGF22/VIM/FN1), T-regulatory (FOXP3/TGFB1/TGFB3), and Janus kinase/JAK (JAK3/STAT1/STAT4) (Fold changes [FCH]>1.5, FDR<.05 for all). Only one protein, ADM, was differentially expressed in FFA serum compared to normal (FCH>1.3, FDR<.05). Significant correlations were found between scalp biomarkers (IL-36RN/IL-25) and FFA severity, as well as between JAK/STAT and fibrosis gene-sets (r>.6; P <.05). Limitations: This study was limited by a small sample size and predominantly female FFA patients. Conclusion: Our data characterize FFA as an inflammatory condition limited to scalp, involving Th1/JAK skewing, with associated fibrosis and elevated T-regulatory markers, suggesting the potential for disease reversibility with JAK/STAT inhibition.

KW - JAK/STAT

KW - OLINK

KW - Th1

KW - alopecia areata

KW - biomarkers

KW - frontal fibrosing alopecia

KW - hair keratins

KW - proteomics

UR - http://www.scopus.com/inward/record.url?scp=85108972445&partnerID=8YFLogxK

U2 - 10.1016/j.jaad.2021.05.016

DO - 10.1016/j.jaad.2021.05.016

M3 - Article

C2 - 34044102

AN - SCOPUS:85108972445

SN - 0190-9622

VL - 86

SP - 551

EP - 562

JO - Journal of the American Academy of Dermatology

JF - Journal of the American Academy of Dermatology

IS - 3

ER -

Scalp and serum profiling of frontal fibrosing alopecia reveals scalp immune and fibrosis dysregulation with no systemic involvement

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Keywords

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