Neutrophil-Related Gene Expression and Low-Density Granulocytes Associated With Disease Activity and Response to Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

Peter C. Grayson; Carmelo Carmona-Rivera; Lijing Xu; Noha Lim; Zhong Gao; Adam L. Asare; Ulrich Specks; John H. Stone; Philip Seo; Robert F. Spiera; Carol A. Langford; Gary S. Hoffman; Cees G. M. Kallenberg; E. William St Clair; Nadia K. Tchao; Steven R. Ytterberg; Deborah J. Phippard; Peter A. Merkel; Mariana J. Kaplan; Paul A. Monach; Rituximab ANCA-Associated

doi:10.1002/art.39153

Neutrophil-Related Gene Expression and Low-Density Granulocytes Associated With Disease Activity and Response to Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

Peter C. Grayson^*, Carmelo Carmona-Rivera, Lijing Xu, Noha Lim, Zhong Gao, Adam L. Asare, Ulrich Specks, John H. Stone, Philip Seo, Robert F. Spiera, Carol A. Langford, Gary S. Hoffman, Cees G. M. Kallenberg, E. William St Clair, Nadia K. Tchao, Steven R. Ytterberg, Deborah J. Phippard, Peter A. Merkel, Mariana J. Kaplan, Paul A. MonachRituximab ANCA-Associated

^*Corresponding author for this work

Translational Immunology Groningen (TRIGR)

Research output: Contribution to journal › Article › Academic › peer-review

105 Citations (Scopus)

Abstract

ObjectiveTo discover biomarkers involved in the pathophysiology of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and to determine whether low-density granulocytes (LDGs) contribute to gene expression signatures in AAV.

MethodsThe source of clinical data and linked biologic specimens was a randomized controlled treatment trial in AAV. RNA sequencing of whole blood from patients with AAV was performed during active disease at the baseline visit and during remission 6 months later. Gene expression was compared between patients who met versus those who did not meet the primary trial outcome of clinical remission at 6 months (responders versus nonresponders). Measurement of neutrophil-related gene expression was confirmed in peripheral blood mononuclear cells (PBMCs) to validate the findings in whole blood. A negative-selection strategy isolated LDGs from PBMC fractions.

ResultsDifferential expression between responders (n=77) and nonresponders (n=35) was detected in 2,346 transcripts at the baseline visit (P

ConclusionIn AAV, increased expression of a granulocyte gene signature is associated with disease activity and decreased response to treatment. The source of this signature is likely LDGs, a potentially pathogenic cell type in AAV.

Original language	English
Pages (from-to)	1922-1932
Number of pages	11
Journal	Arthritis & Rheumatology
Volume	67
Issue number	7
DOIs	https://doi.org/10.1002/art.39153
Publication status	Published - Jul-2015

Keywords

SMALL-VESSEL VASCULITIS
ANCA-ASSOCIATED VASCULITIS
WEGENERS-GRANULOMATOSIS
TREATMENT RESISTANCE
NETTING NEUTROPHILS
EXTRACELLULAR TRAPS
RELAPSE
TRANSCRIPTION
PROTEINASE-3
PREDICTORS

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Grayson, P. C., Carmona-Rivera, C., Xu, L., Lim, N., Gao, Z., Asare, A. L., Specks, U., Stone, J. H., Seo, P., Spiera, R. F., Langford, C. A., Hoffman, G. S., Kallenberg, C. G. M., St Clair, E. W., Tchao, N. K., Ytterberg, S. R., Phippard, D. J., Merkel, P. A., Kaplan, M. J., ... Rituximab ANCA-Associated (2015). Neutrophil-Related Gene Expression and Low-Density Granulocytes Associated With Disease Activity and Response to Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Arthritis & Rheumatology, 67(7), 1922-1932. https://doi.org/10.1002/art.39153

@article{b27d94b0e88c4793bee0d04f4bdf2fd1,

title = "Neutrophil-Related Gene Expression and Low-Density Granulocytes Associated With Disease Activity and Response to Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis",

abstract = "ObjectiveTo discover biomarkers involved in the pathophysiology of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and to determine whether low-density granulocytes (LDGs) contribute to gene expression signatures in AAV.MethodsThe source of clinical data and linked biologic specimens was a randomized controlled treatment trial in AAV. RNA sequencing of whole blood from patients with AAV was performed during active disease at the baseline visit and during remission 6 months later. Gene expression was compared between patients who met versus those who did not meet the primary trial outcome of clinical remission at 6 months (responders versus nonresponders). Measurement of neutrophil-related gene expression was confirmed in peripheral blood mononuclear cells (PBMCs) to validate the findings in whole blood. A negative-selection strategy isolated LDGs from PBMC fractions.ResultsDifferential expression between responders (n=77) and nonresponders (n=35) was detected in 2,346 transcripts at the baseline visit (PConclusionIn AAV, increased expression of a granulocyte gene signature is associated with disease activity and decreased response to treatment. The source of this signature is likely LDGs, a potentially pathogenic cell type in AAV.",

keywords = "SMALL-VESSEL VASCULITIS, ANCA-ASSOCIATED VASCULITIS, WEGENERS-GRANULOMATOSIS, TREATMENT RESISTANCE, NETTING NEUTROPHILS, EXTRACELLULAR TRAPS, RELAPSE, TRANSCRIPTION, PROTEINASE-3, PREDICTORS",

author = "Grayson, {Peter C.} and Carmelo Carmona-Rivera and Lijing Xu and Noha Lim and Zhong Gao and Asare, {Adam L.} and Ulrich Specks and Stone, {John H.} and Philip Seo and Spiera, {Robert F.} and Langford, {Carol A.} and Hoffman, {Gary S.} and Kallenberg, {Cees G. M.} and {St Clair}, {E. William} and Tchao, {Nadia K.} and Ytterberg, {Steven R.} and Phippard, {Deborah J.} and Merkel, {Peter A.} and Kaplan, {Mariana J.} and Monach, {Paul A.} and {Rituximab ANCA-Associated}",

year = "2015",

month = jul,

doi = "10.1002/art.39153",

language = "English",

volume = "67",

pages = "1922--1932",

journal = "Arthritis & Rheumatology",

issn = "2326-5191",

publisher = "Wiley",

number = "7",

}

Grayson, PC, Carmona-Rivera, C, Xu, L, Lim, N, Gao, Z, Asare, AL, Specks, U, Stone, JH, Seo, P, Spiera, RF, Langford, CA, Hoffman, GS, Kallenberg, CGM, St Clair, EW, Tchao, NK, Ytterberg, SR, Phippard, DJ, Merkel, PA, Kaplan, MJ, Monach, PA & Rituximab ANCA-Associated 2015, 'Neutrophil-Related Gene Expression and Low-Density Granulocytes Associated With Disease Activity and Response to Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis', Arthritis & Rheumatology, vol. 67, no. 7, pp. 1922-1932. https://doi.org/10.1002/art.39153

Neutrophil-Related Gene Expression and Low-Density Granulocytes Associated With Disease Activity and Response to Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. / Grayson, Peter C.; Carmona-Rivera, Carmelo; Xu, Lijing et al.
In: Arthritis & Rheumatology, Vol. 67, No. 7, 07.2015, p. 1922-1932.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Neutrophil-Related Gene Expression and Low-Density Granulocytes Associated With Disease Activity and Response to Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

AU - Grayson, Peter C.

AU - Carmona-Rivera, Carmelo

AU - Xu, Lijing

AU - Lim, Noha

AU - Gao, Zhong

AU - Asare, Adam L.

AU - Specks, Ulrich

AU - Stone, John H.

AU - Seo, Philip

AU - Spiera, Robert F.

AU - Langford, Carol A.

AU - Hoffman, Gary S.

AU - Kallenberg, Cees G. M.

AU - St Clair, E. William

AU - Tchao, Nadia K.

AU - Ytterberg, Steven R.

AU - Phippard, Deborah J.

AU - Merkel, Peter A.

AU - Kaplan, Mariana J.

AU - Monach, Paul A.

AU - Rituximab ANCA-Associated

PY - 2015/7

Y1 - 2015/7

N2 - ObjectiveTo discover biomarkers involved in the pathophysiology of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and to determine whether low-density granulocytes (LDGs) contribute to gene expression signatures in AAV.MethodsThe source of clinical data and linked biologic specimens was a randomized controlled treatment trial in AAV. RNA sequencing of whole blood from patients with AAV was performed during active disease at the baseline visit and during remission 6 months later. Gene expression was compared between patients who met versus those who did not meet the primary trial outcome of clinical remission at 6 months (responders versus nonresponders). Measurement of neutrophil-related gene expression was confirmed in peripheral blood mononuclear cells (PBMCs) to validate the findings in whole blood. A negative-selection strategy isolated LDGs from PBMC fractions.ResultsDifferential expression between responders (n=77) and nonresponders (n=35) was detected in 2,346 transcripts at the baseline visit (PConclusionIn AAV, increased expression of a granulocyte gene signature is associated with disease activity and decreased response to treatment. The source of this signature is likely LDGs, a potentially pathogenic cell type in AAV.

AB - ObjectiveTo discover biomarkers involved in the pathophysiology of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and to determine whether low-density granulocytes (LDGs) contribute to gene expression signatures in AAV.MethodsThe source of clinical data and linked biologic specimens was a randomized controlled treatment trial in AAV. RNA sequencing of whole blood from patients with AAV was performed during active disease at the baseline visit and during remission 6 months later. Gene expression was compared between patients who met versus those who did not meet the primary trial outcome of clinical remission at 6 months (responders versus nonresponders). Measurement of neutrophil-related gene expression was confirmed in peripheral blood mononuclear cells (PBMCs) to validate the findings in whole blood. A negative-selection strategy isolated LDGs from PBMC fractions.ResultsDifferential expression between responders (n=77) and nonresponders (n=35) was detected in 2,346 transcripts at the baseline visit (PConclusionIn AAV, increased expression of a granulocyte gene signature is associated with disease activity and decreased response to treatment. The source of this signature is likely LDGs, a potentially pathogenic cell type in AAV.

KW - SMALL-VESSEL VASCULITIS

KW - ANCA-ASSOCIATED VASCULITIS

KW - WEGENERS-GRANULOMATOSIS

KW - TREATMENT RESISTANCE

KW - NETTING NEUTROPHILS

KW - EXTRACELLULAR TRAPS

KW - RELAPSE

KW - TRANSCRIPTION

KW - PROTEINASE-3

KW - PREDICTORS

U2 - 10.1002/art.39153

DO - 10.1002/art.39153

M3 - Article

SN - 2326-5191

VL - 67

SP - 1922

EP - 1932

JO - Arthritis & Rheumatology

JF - Arthritis & Rheumatology

IS - 7

ER -