Identification and stratification of systemic lupus erythematosus patients into two transcriptionally distinct clusters based on IFN-I signature

Abstract

Objective Despite the significant advancement in the understanding of the pathophysiology of systemic lupus erythematosus (SLE) variable clinical response to newer therapies remain a major concern, especially for patients with lupus nephritis and neuropsychiatric systemic lupus erythematosus (NPSLE). We performed this study with an objective to comprehensively characterize Indian SLE patients with renal and neuropsychiatric manifestation with respect to their gene signature, cytokine profile and immune cell phenotypes. Methods We characterized 68 Indian SLE subjects with diverse clinical profiles and disease activity and tried to identify differentially expressed genes and enriched pathways. To understand the temporal profile, same patients were followed at 6 and 12-months intervals. Additionally, auto-antibody profile, levels of various chemokines, cytokines and the proportion of different immune cells and their activation status were captured in these subjects. Results Multiple IFN-related pathways were enriched with significant increase in IFN-I gene signature in SLE patients as compared to normal healthy volunteers (NHV). We identified two transcriptionally distinct clusters within the same cohort of SLE patients with differential immune cell activation status, auto-antibody as well as plasma chemokines and cytokines profile. Conclusions Identification of two distinct clusters of patients based on IFN-I signature provided new insights into the heterogeneity of underlying disease pathogenesis of Indian SLE cohort. Importantly, patient within those clusters retain their distinct expression dynamics of IFN-I signature over the time course of one year despite change in disease activity. This study will guide clinicians and researchers while designing future clinical trials on Indian SLE cohort.

Transcriptomics data: pointing the way to subclassification and personalized medicine in systemic lupus erythematosus

“…IGS+ lupus patients initially were thought to have greater disease activity or severity but more recent studies have indicated that the IGS is persistent in individual patients despite immunosuppressive therapy, does not correlate well with disease activity as measured by the SLE Disease Activity Index (SLEDAI), is correlated with the presence of activated myeloid cells, and appears to be associated with the presence of anti-RNP and/or anti-DNA autoantibodies [1,6 ▪ ]. One group recently reported the stratification of lupus patients into IGS hi and lo in an Indian SLE cohort exhibiting renal and neuropsychiatric disease manifestations, although type I IFN gene expression persisted despite changes in disease activity [7 ▪ ]. Another group additionally carried out stratification of a diverse, multiethnic SLE patient cohort and noted that gene expression and co-expression profiles of IL1RN and TNFSF13B changed in coordination with the IGS longitudinally [8 ▪ ], suggesting IGS status might be informative for selection of therapy.…”