An interleukin 6 responsive plasma cell signature is associated with disease progression in systemic sclerosis interstitial lung disease
Guiquan Jia, Thirumalai R. Ramalingam, Jason A. Vander Heiden, Xia Gao, Daryle J. DePianto, Katrina B. Morshead, Zora Modrušan, Nandhini Ramamoorthi, Paul J. Wolters, Celia J. F. Lin, Dinesh Khanna, Joseph R. Arron
Abstract
Systemic sclerosis (SSc) interstitial lung disease (ILD) is among the leading causes of SSc-related morbidity and mortality. Tocilizumab (TCZ, anti-IL6RA) has demonstrated a reduced rate of pulmonary function decline in two phase 2/3 trials (faSScinate and focuSSced) in SSc-ILD patients. We performed transcriptome analysis of skin biopsy samples collected in the studies to decipher gene networks that were potentially associated with clinical responses to TCZ treatment. One module correlated with disease progression showed pharmacodynamic changes with TCZ treatment, and was characterized by plasma cell (PC) genes. PC signature gene expression levels were also significantly increased in both fibrotic SSc and IPF lungs compared to controls. scRNAseq analyses confirmed that PC signature genes were co-expressed in CD38 and CD138 expressing PC subsets in SSc lungs. These data provide insights into the potential role of PC in disease progression and mechanisms of action of TCZ in fibrotic interstitial lung diseases.