Transcriptome analysis to decipher the molecular underpinnings of response to treatment in systemic lupus erythematosus
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 basel...
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| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2025-03-01
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| Series: | RMD Open |
| Online Access: | https://rmdopen.bmj.com/content/11/1/e005050.full |
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| Summary: | 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. |
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| ISSN: | 2056-5933 |