TY - JOUR
T1 - Cytokine responses in nonlesional psoriatic skin as clinical predictor to anti-TNF agents
AU - Tsoi, Lam C.
AU - Patrick, Matthew T.
AU - Shuai, Shao
AU - Sarkar, Mrinal K.
AU - Chi, Sunyi
AU - Ruffino, Bethany
AU - Billi, Allison C.
AU - Xing, Xianying
AU - Uppala, Ranjitha
AU - Zang, Cheng
AU - Fullmer, Joseph
AU - He, Zhi
AU - Maverakis, Emanual
AU - Mehta, Nehal N.
AU - Perez White, Bethany E.
AU - Getsios, Spiro
AU - Helfrich, Yolanda
AU - Voorhees, John J.
AU - Kahlenberg, J. Michelle
AU - Weidinger, Stephan
AU - Gudjonsson, Johann E.
N1 - Funding Information:
This work was supported by Amgen. L.C.T., M.K.S., and J.E.G. were supported by the Babcock Endowment Fund . The study also received support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant nos. R01-AR060802 and P30-AR075043 to J.E.G. and grant no. AR072129 to L.C.T.), the National Institute of Allergy and Infectious Diseases (award no. R01-AR069071 to J.E.G.), the A. Alfred Taubman Medical Research Institute Kenneth and Frances Eisenberg Emerging Scholar Award (to J.E.G.), Taubman Medical Institute (J.E.G., J.M.K., and L.C.T.), the Dermatology Foundation (L.C.T.), the Arthritis National Research Foundation (L.C.T.), and the National Psoriasis Foundation Psoriasis Prevention Initiative (L.C.T., J.E.G., E.M., and J.M.K.).
Funding Information:
This work was supported by Amgen. L.C.T., M.K.S., and J.E.G. were supported by the Babcock Endowment Fund. The study also received support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant nos. R01-AR060802 and P30-AR075043 to J.E.G. and grant no. AR072129 to L.C.T.), the National Institute of Allergy and Infectious Diseases (award no. R01-AR069071 to J.E.G.), the A. Alfred Taubman Medical Research Institute Kenneth and Frances Eisenberg Emerging Scholar Award (to J.E.G.), Taubman Medical Institute (J.E.G., J.M.K., and L.C.T.), the Dermatology Foundation (L.C.T.), the Arthritis National Research Foundation (L.C.T.), and the National Psoriasis Foundation Psoriasis Prevention Initiative (L.C.T., J.E.G., E.M., and J.M.K.). Disclosure of potential conflict of interest: J. E. Gudjonsson received research grants from AbbVie, AnaptysBio, SunPharma, Genentech, Pfizer, Novartis, Celgene, Almirall, and Eli Lilly, and serves as advisory board member in Novartis, AbbVie, Eli Lilly, MiRagen, BMS/Celgene, AstraZeneca, and Almirall. J. M. Kahlenberg serves on an advisory board for AstraZeneca. The rest of the authors declare that they have no relevant conflicts of interest.
Publisher Copyright:
© 2021 American Academy of Allergy, Asthma & Immunology
PY - 2022/2
Y1 - 2022/2
N2 - Background: A major issue with the current management of psoriasis is our inability to predict treatment response. Objective: Our aim was to evaluate the ability to use baseline molecular expression profiling to assess treatment outcome for patients with psoriasis. Methods: We conducted a longitudinal study of 46 patients with chronic plaque psoriasis treated with anti-TNF agent etanercept, and molecular profiles were assessed in more than 200 RNA-seq samples. Results: We demonstrated correlation between clinical response and molecular changes during the course of the treatment, particularly for genes responding to IL-17A/TNF in keratinocytes. Intriguingly, baseline gene expressions in nonlesional, but not lesional, skin were the best marker of treatment response at week 12. We identified USP18, a known regulator of IFN responses, as positively correlated with Psoriasis Area and Severity Index (PASI) improvement (P = 9.8 × 10−4) and demonstrate its role in regulating IFN/TNF responses in keratinocytes. Consistently, cytokine gene signatures enriched in baseline nonlesional skin expression profiles had strong correlations with PASI improvement. Using this information, we developed a statistical model for predicting PASI75 (ie, 75% of PASI improvement) at week 12, achieving area under the receiver-operating characteristic curve value of 0.75 and up to 80% accurate PASI75 prediction among the top predicted responders. Conclusions: Our results illustrate feasibility of assessing drug response in psoriasis using nonlesional skin and implicate involvement of IFN regulators in anti-TNF responses.
AB - Background: A major issue with the current management of psoriasis is our inability to predict treatment response. Objective: Our aim was to evaluate the ability to use baseline molecular expression profiling to assess treatment outcome for patients with psoriasis. Methods: We conducted a longitudinal study of 46 patients with chronic plaque psoriasis treated with anti-TNF agent etanercept, and molecular profiles were assessed in more than 200 RNA-seq samples. Results: We demonstrated correlation between clinical response and molecular changes during the course of the treatment, particularly for genes responding to IL-17A/TNF in keratinocytes. Intriguingly, baseline gene expressions in nonlesional, but not lesional, skin were the best marker of treatment response at week 12. We identified USP18, a known regulator of IFN responses, as positively correlated with Psoriasis Area and Severity Index (PASI) improvement (P = 9.8 × 10−4) and demonstrate its role in regulating IFN/TNF responses in keratinocytes. Consistently, cytokine gene signatures enriched in baseline nonlesional skin expression profiles had strong correlations with PASI improvement. Using this information, we developed a statistical model for predicting PASI75 (ie, 75% of PASI improvement) at week 12, achieving area under the receiver-operating characteristic curve value of 0.75 and up to 80% accurate PASI75 prediction among the top predicted responders. Conclusions: Our results illustrate feasibility of assessing drug response in psoriasis using nonlesional skin and implicate involvement of IFN regulators in anti-TNF responses.
KW - PASI
KW - Psoriasis
KW - cytokine response
KW - drug response prediction
KW - etanercept
UR - http://www.scopus.com/inward/record.url?scp=85112582147&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85112582147&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2021.07.024
DO - 10.1016/j.jaci.2021.07.024
M3 - Article
C2 - 34343561
AN - SCOPUS:85112582147
SN - 0091-6749
VL - 149
SP - 640-649.e5
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 2
ER -