Baseline peripheral blood mononuclear cell (PBMC) transcriptomics before ustekinumab treatment is linked with Crohn Disease clinical response at 1 year

Background/Objectives: Ustekinumab (Stelara), a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23, is used for Crohn Disease (CD), and the documented clinical remission rate after one year was observed in about 50% of patients. We aimed to identify predictors for a clinical response using peripheral blood obtained from CD patients just before ustekinumab treatment initiation. Methods: RNA extraction from peripheral blood mononuclear cells (PBMC) was followed by mRNA paired-end sequencing. Differential gene expression was performed using DESeq2. Results: We processed samples from 36 adults with CD (13 males, 36%) obtained at baseline before starting ustekinumab treatment. 22/36 (61%) were defined as responders and 14/36 (39%) as non-responders after one year based on Physician Global Assessment (PGA). Differential gene expression between responders (n=22) and non-responders (n=14) did not show a gene expression signature that passed false discovery rate (FDR) correction. However, the analyses identified 68 genes, including CXCL1/2/3, that were induced in non-responders vs. responders with p<0.05 and fold change above 1.5. Functional annotation enrichments of these 68 genes using ToppGene indicated enrichment for cytokine activity (FDR=1.98E-05), CXCR chemokine receptor binding (FDR=2.11E-05), Interleukin-10 signaling (FDR=5.03E-07), Genes encoding secreted soluble factors (FDR=1.73E-05), and Myeloid Dendritic cells (FDR=1.80E-08). Conclusions: No substantial differences were found in PBMC transcriptomics between responders and non-responders. However, among the non-responders, we noted an increased inflammatory response enriched for pathways linked with cytokine activity and chemokine receptor binding, and innate myeloid signature. A larger cohort is required to validate and further explore these findings.