Improvements in immune/melanocyte biomarkers with JAK3/TEC family kinase inhibitor ritlecitinib in vitiligo
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved..
BACKGROUND: Vitiligo is an autoimmune depigmenting disorder with no effective and safe treatments. Its pathogenesis is not fully elucidated.
OBJECTIVE: This substudy of a randomized, double-blind, placebo-controlled phase 2b trial (NCT03715829) evaluated effects of ritlecitinib, an oral JAK3/TEC family kinase inhibitor, on skin and blood biomarkers in participants with nonsegmental vitiligo (NSV).
METHODS: Sixty-five adults with NSV participated in the substudy and received daily treatment for 24 weeks with placebo (n = 14) or ritlecitinib with or without a 4-week loading dose: 200 (loading dose)/50 mg (n = 13), 100/50 mg (n = 12), 50 mg (n = 11), 30 mg (n = 8), or 10 mg (n = 6). Skin (lesional and nonlesional) biopsy samples were obtained at baseline and at 4 and 24 weeks. Changes from baseline to weeks 4 and 24 in skin and blood molecular and cellular biomarkers were evaluated by RNA sequencing, quantitative real-time PCR, proteomic analysis, and flow cytometry.
RESULTS: Ritlecitinib-treated groups showed downregulation of immune biomarkers and upregulation of melanocyte-related markers at weeks 4 and 24 compared to baseline and/or placebo. Significant reductions were seen in CD3+/CD8+ T-cell infiltrates, with significant increases in melanocyte markers (tyrosinase; Melan-A) in NSV lesions in the 50 mg ritlecitinib groups (both P < .05). There was significant, dose-dependent downregulation in T-cell activation, NK, cytotoxic, and regulatory markers in lesional skin (IL-2, IL2-RA, IL-15, CCR7, CD5, CRTAM, NCR1, XCL1, KIR3DL1, FASLG, KLRD; P < .05). TH1 and TH2 markers were also downregulated in lesional skin and blood in a dose-dependent manner (P < .05). Changes in immune biomarkers correlated with clinical response.
CONCLUSIONS: Ritlecitinib significantly downregulated proinflammatory biomarkers and increased melanocyte products in skin and blood of participants with NSV, suggesting its potential in treatment. Ritlecitinib-mediated changes positively correlated with clinical response.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:153 |
|---|---|
| Enthalten in: |
The Journal of allergy and clinical immunology - 153(2024), 1 vom: 13. Jan., Seite 161-172.e8 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Guttman-Yassky, Emma [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 08.01.2024 Date Revised 16.02.2024 published: Print-Electronic ClinicalTrials.gov: NCT03715829 Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.jaci.2023.09.021 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM362729433 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM362729433 | ||
| 003 | DE-627 | ||
| 005 | 20240216232628.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.jaci.2023.09.021 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1295.xml |
| 035 | |a (DE-627)NLM362729433 | ||
| 035 | |a (NLM)37777018 | ||
| 035 | |a (PII)S0091-6749(23)01202-2 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Guttman-Yassky, Emma |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Improvements in immune/melanocyte biomarkers with JAK3/TEC family kinase inhibitor ritlecitinib in vitiligo |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 08.01.2024 | ||
| 500 | |a Date Revised 16.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT03715829 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a BACKGROUND: Vitiligo is an autoimmune depigmenting disorder with no effective and safe treatments. Its pathogenesis is not fully elucidated | ||
| 520 | |a OBJECTIVE: This substudy of a randomized, double-blind, placebo-controlled phase 2b trial (NCT03715829) evaluated effects of ritlecitinib, an oral JAK3/TEC family kinase inhibitor, on skin and blood biomarkers in participants with nonsegmental vitiligo (NSV) | ||
| 520 | |a METHODS: Sixty-five adults with NSV participated in the substudy and received daily treatment for 24 weeks with placebo (n = 14) or ritlecitinib with or without a 4-week loading dose: 200 (loading dose)/50 mg (n = 13), 100/50 mg (n = 12), 50 mg (n = 11), 30 mg (n = 8), or 10 mg (n = 6). Skin (lesional and nonlesional) biopsy samples were obtained at baseline and at 4 and 24 weeks. Changes from baseline to weeks 4 and 24 in skin and blood molecular and cellular biomarkers were evaluated by RNA sequencing, quantitative real-time PCR, proteomic analysis, and flow cytometry | ||
| 520 | |a RESULTS: Ritlecitinib-treated groups showed downregulation of immune biomarkers and upregulation of melanocyte-related markers at weeks 4 and 24 compared to baseline and/or placebo. Significant reductions were seen in CD3+/CD8+ T-cell infiltrates, with significant increases in melanocyte markers (tyrosinase; Melan-A) in NSV lesions in the 50 mg ritlecitinib groups (both P < .05). There was significant, dose-dependent downregulation in T-cell activation, NK, cytotoxic, and regulatory markers in lesional skin (IL-2, IL2-RA, IL-15, CCR7, CD5, CRTAM, NCR1, XCL1, KIR3DL1, FASLG, KLRD; P < .05). TH1 and TH2 markers were also downregulated in lesional skin and blood in a dose-dependent manner (P < .05). Changes in immune biomarkers correlated with clinical response | ||
| 520 | |a CONCLUSIONS: Ritlecitinib significantly downregulated proinflammatory biomarkers and increased melanocyte products in skin and blood of participants with NSV, suggesting its potential in treatment. Ritlecitinib-mediated changes positively correlated with clinical response | ||
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a JAK | |
| 650 | 4 | |a Janus kinase inhibitors | |
| 650 | 4 | |a Vitiligo | |
| 650 | 4 | |a biomarkers | |
| 650 | 4 | |a cytokines | |
| 650 | 4 | |a inflammation | |
| 650 | 4 | |a melanocytes | |
| 650 | 4 | |a nonsegmental vitiligo | |
| 650 | 4 | |a ritlecitinib | |
| 650 | 4 | |a tyrosine kinase | |
| 650 | 7 | |a Biomarkers |2 NLM | |
| 650 | 7 | |a JAK3 protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.10.2 |2 NLM | |
| 650 | 7 | |a Janus Kinase 3 |2 NLM | |
| 650 | 7 | |a EC 2.7.10.2 |2 NLM | |
| 700 | 1 | |a Del Duca, Ester |e verfasserin |4 aut | |
| 700 | 1 | |a Da Rosa, Joel Correa |e verfasserin |4 aut | |
| 700 | 1 | |a Bar, Jonathan |e verfasserin |4 aut | |
| 700 | 1 | |a Ezzedine, Khaled |e verfasserin |4 aut | |
| 700 | 1 | |a Ye, Zhan |e verfasserin |4 aut | |
| 700 | 1 | |a He, Wen |e verfasserin |4 aut | |
| 700 | 1 | |a Hyde, Craig |e verfasserin |4 aut | |
| 700 | 1 | |a Hassan-Zahraee, Mina |e verfasserin |4 aut | |
| 700 | 1 | |a Yamaguchi, Yuji |e verfasserin |4 aut | |
| 700 | 1 | |a Peeva, Elena |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t The Journal of allergy and clinical immunology |d 1971 |g 153(2024), 1 vom: 13. Jan., Seite 161-172.e8 |w (DE-627)NLM000018449 |x 1097-6825 |7 nnns |
| 773 | 1 | 8 | |g volume:153 |g year:2024 |g number:1 |g day:13 |g month:01 |g pages:161-172.e8 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.jaci.2023.09.021 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 153 |j 2024 |e 1 |b 13 |c 01 |h 161-172.e8 | ||