Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease
© 2021 by The American Society of Hematology..
Idiopathic multicentric Castleman disease (iMCD) is a poorly understood hematologic disorder involving cytokine-induced polyclonal lymphoproliferation, systemic inflammation, and potentially fatal multiorgan failure. Although the etiology of iMCD is unknown, interleukin-6 (IL-6) is an established disease driver in approximately one-third of patients. Anti-IL-6 therapy, siltuximab, is the only US Food and Drug Administration-approved treatment. Few options exist for siltuximab nonresponders, and no validated tests are available to predict likelihood of response. We procured and analyzed the largest-to-date cohort of iMCD samples, which enabled classification of iMCD into disease categories, discovery of siltuximab response biomarkers, and identification of therapeutic targets for siltuximab nonresponders. Proteomic quantification of 1178 analytes was performed on serum of 88 iMCD patients, 60 patients with clinico-pathologically overlapping diseases (human herpesvirus-8-associated MCD, N = 20; Hodgkin lymphoma, N = 20; rheumatoid arthritis, N = 20), and 42 healthy controls. Unsupervised clustering revealed iMCD patients have heterogeneous serum proteomes that did not cluster with clinico-pathologically overlapping diseases. Clustering of iMCD patients identified a novel subgroup with superior response to siltuximab, which was validated using a 7-analyte panel (apolipoprotein E, amphiregulin, serum amyloid P-component, inactivated complement C3b, immunoglobulin E, IL-6, erythropoietin) in an independent cohort. Enrichment analyses and immunohistochemistry identified Janus kinase (JAK)/signal transducer and activator of transcription 3 signaling as a candidate therapeutic target that could potentially be targeted with JAK inhibitors in siltuximab nonresponders. Our discoveries demonstrate the potential for accelerating discoveries for rare diseases through multistakeholder collaboration.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:5 |
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| Enthalten in: |
Blood advances - 5(2021), 17 vom: 14. Sept., Seite 3445-3456 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Pierson, Sheila K [VerfasserIn] |
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| Links: |
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| Themen: |
Interleukin-6 |
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| Anmerkungen: |
Date Completed 01.11.2021 Date Revised 01.11.2021 published: Print Citation Status MEDLINE |
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| doi: |
10.1182/bloodadvances.2020004016 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM329813579 |
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| 100 | 1 | |a Pierson, Sheila K |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease |
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| 500 | |a Date Revised 01.11.2021 | ||
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2021 by The American Society of Hematology. | ||
| 520 | |a Idiopathic multicentric Castleman disease (iMCD) is a poorly understood hematologic disorder involving cytokine-induced polyclonal lymphoproliferation, systemic inflammation, and potentially fatal multiorgan failure. Although the etiology of iMCD is unknown, interleukin-6 (IL-6) is an established disease driver in approximately one-third of patients. Anti-IL-6 therapy, siltuximab, is the only US Food and Drug Administration-approved treatment. Few options exist for siltuximab nonresponders, and no validated tests are available to predict likelihood of response. We procured and analyzed the largest-to-date cohort of iMCD samples, which enabled classification of iMCD into disease categories, discovery of siltuximab response biomarkers, and identification of therapeutic targets for siltuximab nonresponders. Proteomic quantification of 1178 analytes was performed on serum of 88 iMCD patients, 60 patients with clinico-pathologically overlapping diseases (human herpesvirus-8-associated MCD, N = 20; Hodgkin lymphoma, N = 20; rheumatoid arthritis, N = 20), and 42 healthy controls. Unsupervised clustering revealed iMCD patients have heterogeneous serum proteomes that did not cluster with clinico-pathologically overlapping diseases. Clustering of iMCD patients identified a novel subgroup with superior response to siltuximab, which was validated using a 7-analyte panel (apolipoprotein E, amphiregulin, serum amyloid P-component, inactivated complement C3b, immunoglobulin E, IL-6, erythropoietin) in an independent cohort. Enrichment analyses and immunohistochemistry identified Janus kinase (JAK)/signal transducer and activator of transcription 3 signaling as a candidate therapeutic target that could potentially be targeted with JAK inhibitors in siltuximab nonresponders. Our discoveries demonstrate the potential for accelerating discoveries for rare diseases through multistakeholder collaboration | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 700 | 1 | |a Shenoy, Sushila |e verfasserin |4 aut | |
| 700 | 1 | |a Oromendia, Ana B |e verfasserin |4 aut | |
| 700 | 1 | |a Gorzewski, Alexander M |e verfasserin |4 aut | |
| 700 | 1 | |a Langan Pai, Ruth-Anne |e verfasserin |4 aut | |
| 700 | 1 | |a Nabel, Christopher Shield |e verfasserin |4 aut | |
| 700 | 1 | |a Ruth, Jason R |e verfasserin |4 aut | |
| 700 | 1 | |a Parente, Sophia A T |e verfasserin |4 aut | |
| 700 | 1 | |a Arenas, Daniel J |e verfasserin |4 aut | |
| 700 | 1 | |a Guilfoyle, Mary |e verfasserin |4 aut | |
| 700 | 1 | |a Reddy, Manjula |e verfasserin |4 aut | |
| 700 | 1 | |a Weinblatt, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Shadick, Nancy |e verfasserin |4 aut | |
| 700 | 1 | |a Bower, Mark |e verfasserin |4 aut | |
| 700 | 1 | |a Pria, Alessia Dalla |e verfasserin |4 aut | |
| 700 | 1 | |a Masaki, Yasufumi |e verfasserin |4 aut | |
| 700 | 1 | |a Katz, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Mezey, Jason |e verfasserin |4 aut | |
| 700 | 1 | |a Beineke, Philip |e verfasserin |4 aut | |
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| 700 | 1 | |a Tendler, Craig |e verfasserin |4 aut | |
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| 700 | 1 | |a Fosså, Alexander |e verfasserin |4 aut | |
| 700 | 1 | |a van Rhee, Frits |e verfasserin |4 aut | |
| 700 | 1 | |a Fajgenbaum, David C |e verfasserin |4 aut | |
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