RNA sequencing to predict response to TNF-α inhibitors reveals possible mechanism for nonresponse in smokers.

Autor:	Cuppen BVJ; a Rheumatology & Clinical Immunology , University Medical Center Utrecht , Utrecht , The Netherlands., Rossato M; b Laboratory of Translational Immunology , University Medical Center Utrecht , Utrecht , The Netherlands.; c Department of Biotechnology , University of Verona , Verona , Italy., Fritsch-Stork RDE; a Rheumatology & Clinical Immunology , University Medical Center Utrecht , Utrecht , The Netherlands.; d 1st Medical Department & Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling , Hanusch Hospital , Vienna , Austria.; e Sigmund Freud University , Vienna , Austria., Concepcion AN; a Rheumatology & Clinical Immunology , University Medical Center Utrecht , Utrecht , The Netherlands., Linn-Rasker SP; f Rheumatology , Meander Medisch Centrum , Amersfoort , Netherlands., Bijlsma JWJ; a Rheumatology & Clinical Immunology , University Medical Center Utrecht , Utrecht , The Netherlands., van Laar JM; a Rheumatology & Clinical Immunology , University Medical Center Utrecht , Utrecht , The Netherlands., Lafeber FPJG; a Rheumatology & Clinical Immunology , University Medical Center Utrecht , Utrecht , The Netherlands., Radstake TR; a Rheumatology & Clinical Immunology , University Medical Center Utrecht , Utrecht , The Netherlands.; b Laboratory of Translational Immunology , University Medical Center Utrecht , Utrecht , The Netherlands.
Jazyk:	angličtina
Zdroj:	Expert review of clinical immunology [Expert Rev Clin Immunol] 2018 Jul; Vol. 14 (7), pp. 623-633. Date of Electronic Publication: 2018 Jun 06.
DOI:	10.1080/1744666X.2018.1480937
Abstrakt:	Background: Several studies have employed microarray-based profiling to predict response to tumor necrosis factor-alpha inhibitors (TNFi) in rheumatoid arthritis (RA); yet efforts to validate these targets have failed to show predictive abilities acceptable for clinical practice. Methods: The eighty most extreme responders and nonresponders to TNFi therapy were selected from the observational BiOCURA cohort. RNA sequencing was performed on mRNA from peripheral blood mononuclear cells (PBMCs) collected before initiation of treatment. The expression of pathways as well as individual gene transcripts between responders and nonresponders was investigated. Promising targets were technically replicated and validated in n = 40 new patients using qPCR assays. Results: Before therapy initiation, nonresponders had lower expression of pathways related to interferon and cytokine signaling, while also showing higher levels of two genes, GPR15 and SEMA6B (p = 0.02). The two targets could be validated, however, additional analyses revealed that GPR15 and SEMA6B did not independently predict response, but were rather dose-dependent markers of smoking (p < 0.0001). Conclusions: The study did not identify new transcripts ready to use in clinical practice, yet GPR15 and SEMA6B were recognized as candidate explanatory markers for the reduced treatment success in RA smokers.
Databáze:	MEDLINE
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