Background and aims Repository corticotropin injection (RCI; H.P. Acthar Gel) is a porcine pituitary-derived ACTH preparation approved by the FDA for therapy in selected cases of SLE. Previous studies have shown that RCI directly inhibits human B cell function in vitro.

Methods We used RNA-Seq to identify elements of the transcriptome that are acutely modulated by RCI in human B cells activated in vitro by IL4 and CD40 ligand. We compared RCI effects to those of a synthetic glucocorticoid (dexamethasone; Dex) under the same conditions.

Results 115 unique gene transcripts were significantly and reproducibly upregulated by RCI after 24 hours in culture. Pathways analysis revealed that upregulated genes were over-represented in “immune system response” (2.8-fold; p=0.026) and “response to stress” (4.16-fold; p=0.0069). 74 gene transcripts were down-regulated by RCI, and these were over-represented in two pathways: “immune system response” (2.91-fold; p=0.035) and “cellular process” (1.73-fold; p=0.0036). In Dex-treated cells, 65 gene transcripts were upregulated and 23 gene transcripts were down-regulated. There was no overlap between the set of genes upregulated by RCI and Dex. Two genes (PARM1 and RANKL) were downregulated by both RCI and Dex. Pathways analysis of Dex- treated samples did not reveal significant overrepresentation of regulated genes in any specific ontologic pathway.

Conclusions These data suggest that RCI exerts direct effects on human B cells to acutely modulate gene expression. These effects are distinct from those of glucocorticoids, supporting potential differences in mechanism of action of these two agents for treatment of autoimmune diseases.