Serum Proteomics Reveals Distinct Subtypes Associated with Treatment Response in Idiopathic Multicentric Castleman Disease
| العنوان: | Serum Proteomics Reveals Distinct Subtypes Associated with Treatment Response in Idiopathic Multicentric Castleman Disease |
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| المؤلفون: | David C. Fajgenbaum, Philip Beineke, Jason R. Ruth, Manjula Reddy, Sheila K Pierson, Dustin Shilling, Laura M. Katz, Sofija Miljovska, Yasufumi Masaki, Jef Benbanaste, Alessia Dalla Pria, Michael E. Weinblatt, David M. Lee, Jason G. Mezey, Mark Bower, Mary Guilfoyle, Alexander Fosså, Christopher S. Nabel, Jeff Wiser, Frits van Rhee, Craig Tendler, Nancy A. Shadick, Ana B Oromendia, Sushila A. Shenoy |
| المصدر: | Blood. 132:3716-3716 |
| بيانات النشر: | American Society of Hematology, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Pathology, medicine.medical_specialty, Predictive marker, biology, business.industry, Immunology, Lymphoproliferative disorders, Cell Biology, Hematology, medicine.disease, Proteomics, Biochemistry, Siltuximab, chemistry.chemical_compound, chemistry, Rheumatoid arthritis, Proteome, medicine, biology.protein, business, Interleukin 6, Cytokine storm |
| الوصف: | Human herpesvirus-8(HHV-8)-negative/idiopathic multicentric Castleman disease (iMCD) is a rare and poorly understood disorder diagnosed in ~1,000 individuals in the USA each year. It involves polyclonal lymphoproliferation, constitutional symptoms, systemic inflammation and an uncontrollable cytokine storm resulting in life-threatening multi-organ failure. Diagnosis and treatment can be difficult due to limited etiological understanding and heterogeneous presentation - clinical, laboratory, and histopathological abnormalities overlap with infectious, autoimmune and oncological diseases. iMCD symptoms and disease progression are largely believed to be driven by interleukin-6 (IL-6). However, approximately 66% of iMCD patients did not respond to anti-IL-6 therapy, siltuximab, the only FDA-approved iMCD therapy, in its phase II study (NCT01024036). Few treatment options exist for anti-IL-6 refractory patients because alternative driver cytokines and signaling pathways are not known. Herein we report the largest study to-date of iMCD serum proteomes with correlative anti-IL6 response data from 92 iMCD patients in disease flare (n=75 of which were collected as part of NCT01024036), in order to: (1) molecularly define iMCD, (2) identify predictors of response to anti-IL6 therapy, and (3) gain insights into the pathogenesis of iMCD. Proteomes of HHV8-positive MCD (n=20), Hodgkin lymphoma (n=20), rheumatoid arthritis (n=20) and healthy individuals (n=44) were also analyzed. Of the ~1,300 analytes measured using SomaLogic SOMAscan, 1,178 passed QC and were included in analyses. Each analyte was log2 transformed and capped at the 2.5th and 97.5th percentiles. Clinical and laboratory data collected at the time of sample draw were used to calculate disease activity following a modified CHAP scale: C-reactive protein, hemoglobin and albumin; missing performance status. Response to siltuximab was determined in NCT01024036. Data analysis was performed using the Medidata Rave Omics machine learning platform and R v3.4.4. Clustering of baseline proteomic data for iMCD patients identified six clusters that ranged in size from seven to 27 subjects. No associations with race, site, sex, age, or batch were found. Analytes identified among the strongest differentiators include cytokines, chemokines and inflammatory molecules. Interestingly, the largest cluster was associated with response to siltuximab (p Disclosures Guilfoyle: Janssen Pharmaceuticals, Inc.: Employment. Tendler:Janssen Pharmaceuticals, Inc.: Employment, Equity Ownership. Reddy:Janssen Pharmaceuticals, Inc.: Employment, Equity Ownership. Weinblatt:Amgen: Consultancy, Research Funding; Sanofi/Regeneron: Consultancy, Research Funding; Crescendo Bioscience: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; UCB Pharmaceuticals: Consultancy, Research Funding. Bower:Merck: Honoraria; ViiV: Honoraria; Gilead: Honoraria; Janssen Pharmaceuticals: Honoraria. Masaki:Ono: Research Funding; Phizer: Research Funding; Astellas: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin: Research Funding. Beineke:Medidata Solutions: Employment, Equity Ownership. Miljovska:Medidata Solutions: Employment. Katz:Medidata Solutions: Employment. Shenoy:Medidata Solutions: Consultancy. Oromendia:Medidata Solutions: Employment, Equity Ownership. Mezey:Medidata Solutions: Consultancy. Wiser:Medidata Solutions: Employment, Equity Ownership. Benbanaste:Medidata Solutions: Employment, Equity Ownership. Lee:Medidata Solutions: Employment. Fosså:Janssen Pharmaceuticals, Inc.: Honoraria. Fajgenbaum:Janssen Pharmaceuticals, Inc.: Research Funding. |
| تدمد: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2018-99-119135 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::a6c3be1110f77d381f5aa4434e8c5b5a https://doi.org/10.1182/blood-2018-99-119135 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi...........a6c3be1110f77d381f5aa4434e8c5b5a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15280020 00064971 |
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| DOI: | 10.1182/blood-2018-99-119135 |