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Baseline Peripheral Blood Mononuclear Cell Transcriptomics Before Ustekinumab Treatment Is Linked With Crohn's
Maya Granot1, Tzipi Braun1, Gilat Efroni1
1Pediatric Gastroenterology and Nutrition Unit, Sheba Medical Center, Tel-HaShomer, affiliated with the Tel-Aviv University, Tel-Aviv, Israel.
Insights
Predicting Crohn's disease response to ustekinumab is challenging. Nonresponders showed increased inflammatory gene expression, particularly related to cytokine activity and myeloid cells, suggesting potential biomarkers for treatment outcomes.
Area of Science:
- Immunology
- Gastroenterology
- Genomics
Background:
- Ustekinumab, a biologic targeting IL-12/23, treats Crohn's disease (CD) with ~50% remission rates.
- Predicting patient response to ustekinumab is crucial for optimizing treatment strategies.
Purpose of the Study:
- To identify baseline peripheral blood gene expression predictors of clinical response to ustekinumab in CD patients.
- To investigate transcriptomic differences between ustekinumab responders and nonresponders.
Main Methods:
- RNA sequencing of peripheral blood mononuclear cells from 36 CD patients before ustekinumab initiation.
- Differential gene expression analysis using DESeq2 and functional enrichment analysis with ToppGene.
Main Results:
- No significant gene expression signature distinguished responders from nonresponders after FDR correction.
- However, 68 genes, including CXCL1/2/3, were upregulated in nonresponders (P < 0.05, fold change > 1.5).
- Enrichment analysis revealed pathways related to cytokine activity, chemokine receptor binding, IL-10 signaling, and myeloid cell signatures in nonresponders.
Conclusions:
- Baseline peripheral blood transcriptomics showed no clear predictive signature for ustekinumab response in CD.
- Nonresponders exhibited an enhanced inflammatory profile, suggesting potential biomarkers for further investigation.
- Larger cohorts are needed to validate these preliminary findings and explore their clinical utility.
Introduction:
Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin (IL)-12 and IL-23, is used for Crohn's disease (CD), and the documented clinical remission rate after 1 year was observed in approximately 50% of patients. We aimed to identify predictors for a clinical response using peripheral blood obtained from patients with CD just before ustekinumab treatment initiation.
Methods:
RNA extraction from peripheral blood mononuclear cells was followed by mRNA paired-end sequencing. Differential gene expression was performed using DESeq2.
Results:
We processed samples from 36 adults with CD (13 men, 36%) obtained at baseline before starting ustekinumab treatment. Twenty-two of 36 (61%) were defined as responders and 14/36 (39%) as nonresponders after 1 year based on Physician Global Assessment. Differential gene expression between responders (n = 22) and nonresponders (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, which were induced in nonresponders 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), IL-10 signaling (FDR = 5.03E-07), genes encoding secreted soluble factors (FDR = 1.73E-05), and myeloid dendritic cells (FDR = 1.80E-08).
Discussion:
No substantial differences were found in peripheral blood mononuclear cell transcriptomics between responders and nonresponders. However, among the nonresponders, 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.
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