Transcriptome analysis to decipher the molecular underpinnings of response to treatment in systemic lupus erythematosus.

Abstract

Objective: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterised by variable treatment responses. We investigated the transcriptional landscape associated with treatment response and resistance in SLE.

Methods: Blood was collected from 92 active patients with SLE at baseline and after 6 months (n=32 paired samples) of treatment with cyclophosphamide (n=40), rituximab (n=20), belimumab (n=23), mycophenolate mofetil (n=8) or azathioprine (n=1) and was subjected to RNA sequencing. The response was defined by the Lupus Low Disease Activity State. We identified differentially expressed genes and co-expressed transcript modules.

Results: Achieving response, irrespective of treatment, was accompanied by downregulation of B cell immunity-related and complement activation-related signatures. Rituximab led to the most profound decrease in the activity of the B cell pathway, while cyclophosphamide uniquely downregulated neutrophil activation pathways. Responders, regardless of medication, showed increased activity in pathways related to neutrophil migration, type I interferon signalling, complement activation and B cell function prior to treatment. A 539-gene signature, enriched in processes related to chemokine signalling, characterised patients with insufficient response to treatment.

Conclusions: Baseline B cell immunity transcriptional signatures correlate with favourable treatment outcomes-accounting for better responses in serologically active patients in SLE clinical trials-with effective treatment reversing the B cell immunity signature. Cyclophosphamide uniquely targets a neutrophil gene signature linked to severe SLE. Alterations in chemotaxis may represent a mechanism driving resistance to treatment in SLE.