Peripheral blood transcriptomic analysis of patients with rheumatoid arthritis associated interstitial lung disease reveals: distinct molecular signature with evidence of humoral and myeloid immunity.

Abstract

Background: Interstitial lung disease (ILD) is a significant cause of morbidity and mortality in rheumatoid arthritis (RA). RNA sequencing (RNA-seq) of peripheral blood may provide an unbiased look at pathogenetic events involved.

Methods: Peripheral blood was collected from RA-ILD (n = 11), RA non-ILD (n = 10), psoriatic arthritis (PsA, n = 23)patients and healthy controls (HC, n = 7) for transcriptomic analysis. All patients in the RA-ILD group were under treatment during sampling, GC and cDMARDs. The gene expression profile of RA ILD was inferred through differential gene expression analysis followed by pathway and enrichment analysis. Further transcriptomic analysis was conducted based on radiological pattern, clinical progression through Modified Medical Research Council (mMRC) Dyspnea scale, and radiological progression. Drug repurposing analysis was performed to identify perturbagens that counteract RA-ILD-specific signatures. To identify shared pathways between SSc and RA we used publicly available RNA-seq data of patients with systemic sclerosis-associated ILD (SSc-ILD).

Results: In RA-ILD patients, differential expression analysis revealed enrichment in immune response pathways, metabolism, IFNα and IFNγ response. Within the RA-ILD subgroup, differential expression analysis of clinical and/or radiological progressors versus non-progressors revealed enriched pathways related to cell cycle, DNA replication, IFNγ response, inflammasome assembly and negative regulation of immune response in progressors. Drug repurposing analysis revealed that ITK, Syk and FAK inhibitors are candidate compounds that potentially reverse the transcriptomic signature of RA-ILD progression. Comparison of RA-ILD and SSc revealed shared pathways related to metabolism, extracellular matrix, IFNγ response and response to microorganisms.

Conclusions: In this preliminary study, RA-ILD patients exhibit enhanced immune responses, metabolism and cytokine activation. These data need to be further validated in larger studies.