Abstract
Infliximab (IFX) is an effective medication for ulcerative colitis (UC) patients. However, one-third of UC patients show primary non-response (PNR) to IFX. Our study analyzed three Gene Expression Omnibus (GEO) datasets and used the RobustRankAggreg (RRA) algorithm to assist in identifying differentially expressed genes (DEGs) between IFX responders and non-responders. Then, an artificial intelligence (AI) technology, artificial neural network (ANN) analysis, was applied to validate the predictive value of the selected genes. The results showed that the combination of CDX2, CHP2, HSD11B2, RANK, NOX4, and VDR is a good predictor of patients’ response to IFX therapy. The range of repeated overall area under the receiver-operating characteristic curve (AUC) was 0.850 ± 0.103. Moreover, we used an independent GEO dataset to further verify the value of the six DEGs in predicting PNR to IFX, which has a range of overall AUC of 0.759 ± 0.065. Since protein detection did not require fresh tissue and can avoid multiple biopsies, our study tried to discover whether the key information, analyzed by RNA levels, is suitable for protein detection. Therefore, immunohistochemistry (IHC) staining of colonic biopsy tissues from UC patients treated with IFX and a receiver-operating characteristic (ROC) analysis were used to further explore the clinical application value of the six DEGs at the protein level. The IHC staining of colon tissues from UC patients confirmed that VDR and RANK are significantly associated with IFX efficacy. Total IHC scores lower than 5 for VDR and lower than 7 for RANK had an AUC of 0.828 (95% CI: 0.665–0.991, p = 0.013) in predicting PNR to IFX. Collectively, we identified a predictive RNA model for PNR to IFX and explored an immune-related protein model based on the RNA model, including VDR and RANK, as a predictor of IFX non-response, and determined the cutoff value. The result showed a connection between the RNA and protein model, and both two models were available. However, the composite signature of VDR and RANK is more conducive to clinical application, which could be used to guide the preselection of patients who might benefit from pharmacological treatment in the future.
Highlights
Ulcerative colitis (UC) is a chronic relapsing inflammatory disease of the colonic mucosa
We found that 1) the non-responders to IFX tended to have a lower pretreatment expression of the downregulated Differentially Expressed Genes (DEGs) compared with the responders; 2) the posttreatment expression of the downregulated DEGs displayed a trend of increases in the responders; and 3) the expression of the downregulated DEGs after treatment in those who responded to IFX was higher than that in those who did not respond to IFX
Our study extracted DEGs from a publicly available database and identified several gene signatures of patients diagnosed with UC with primary non-response to IFX based on the RRA algorithm, gastrointestinal expression, and previous studies, including CDX2, CHP2, HSD11B2, Receptor activator of nuclear factor kB (RANK), NOX4, and VDR
Summary
Ulcerative colitis (UC) is a chronic relapsing inflammatory disease of the colonic mucosa. The mainstay therapies for UC include 5-aminosalicylates, glucocorticoids, immunosuppressants, and biologic agents [1, 2]. Biologic drugs, including antitumor necrosis factor (TNF)-a agents, anti-integrin drugs (vedolizumab), Janus kinase inhibitors (tofacitinib), and interleukin-12/23 antibodies (ustekinumab) [3], have driven UC therapy to a new era. According to previous studies, nearly onethird of UC patients show primary non-response (PNR). Studies have shown that other biologic agents have a higher failure rate in patients who previously failed to respond to IFX treatment than in those who are naïve to anti-TNF treatment [6, 7]. The time PNR patients spend on IFX therapy can delay treatment, increase the risk of disease aggravation, and increase the economic burden of UC. An approach to identify markers from common, accessible samples, such as tissue biopsies or blood samples, is needed
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