Peripheral Blood Gene Expression Profiling Shows Predictive Significance for Response to Mycophenolate in Systemic Sclerosis-Related Interstitial Lung Disease

Authors

Shervin Assassi
Elizabeth R Volkmann
W Jim Zheng
Xuan Wang
Holly Wilhalme
Marka A Lyons
Michael D Roth
Donald P Tashkin

Publication Date

6-1-2022

Journal

Annals of the Rheumatic Diseases

Abstract

OBJECTIVES: To characterise the peripheral blood cell (PBC) gene expression changes ensuing from mycophenolate mofetil (MMF) or cyclophosphamide (CYC) treatment and to determine the predictive significance of baseline PBC transcript scores for response to immunosuppression in systemic sclerosis (SSc)-related interstitial lung disease (ILD).

METHODS: PBC RNA samples from baseline and 12-month visits, corresponding to the active treatment period of both arms in Scleroderma Lung Study II, were investigated by global RNA sequencing. Joint models were created to examine the predictive significance of

RESULTS: 134 patients with SSc-ILD (CYC=69 and MMF=65) were investigated. CYC led to an upregulation of erythropoiesis, inflammation and myeloid lineage-related modules and a downregulation of lymphoid lineage-related modules. The modular changes resulting from MMF treatment were more modest and included a downregulation of plasmablast module. In the longitudinal analysis, none of the baseline transcript module scores showed predictive significance for FVC% course in the CYC arm. In contrast, in the MMF arm, higher baseline lymphoid lineage modules predicted better subsequent FVC% course, while higher baseline myeloid lineage and inflammation modules predicted worse subsequent FVC% course.

CONCLUSION: Consistent with the primary mechanism of action of MMF on lymphocytes, patients with SSc-ILD with higher baseline lymphoid module scores had better FVC% course, while those with higher myeloid cell lineage activation score had poorer FVC% course on MMF.

Keywords

Cyclophosphamide, Gene Expression Profiling, Humans, Immunosuppressive Agents, Inflammation, Lung, Lung Diseases, Interstitial, Mycophenolic Acid, Scleroderma, Systemic, Vital Capacity, scleroderma, systemic, pulmonary fibrosis, autoimmune diseases

DOI

10.1136/annrheumdis-2021-221313

PMID

35190386

PMCID

PMC9117450

PubMedCentral® Posted Date

2-21-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes