Development of Predictive Models for Long-Term Endoscopic Response to Ustekinumab in Crohn’s Disease Based on Plasma Proteomics

Chenchen Wu,1 Jiawen Zheng,2 Xin Qian,3 Chunyan Peng,4 Fan Zhou,4 Lei Wang1,4 1Department of Gastroenterology, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, People’s Republic of China; 2Zhenjiang Hospital of Chinese Traditional and Western Medicine, Zhenjiang, People’s Republic of China; 3Department of Gastroenterology, Nanjing Drum Tower Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 4Department of Gastroenterology, Nanjing Drum Tower Hospital Affiliated with Medical School of Nanjing University, Nanjing, People’s Republic of ChinaCorrespondence: Fan Zhou, Department of Gastroenterology, Nanjing Drum Tower Hospital, Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, Jiangsu, 210008, People’s Republic of China, Tel +86-15895969717, Email [email protected] Lei Wang, Department of Gastroenterology, Nanjing Drum Tower Hospital, Clinical College of Jiangsu University, Nanjing, Jiangsu, 210008, People’s Republic of China, Tel +86-13851579216, Email [email protected]: Ustekinumab (UST) is effective for Crohn’s disease (CD), yet reliable biomarkers for predicting long-term response remain scarce. This study aimed to identify novel plasma proteomic biomarkers and develop predictive models for long-term endoscopic response to UST therapy in patients.Methods: Baseline plasma inflammatory proteins were profiled using the Olink platform in 40 CD patients treated with UST (20 responders, 20 non-responders). Differentially expressed proteins (DEPs) were identified after adjusting for age, age at diagnosis, and SES-CD scores. Stable DEPs were selected via bootstrap resampling and further validated in an independent patient group from the same center (n=20) using ELISA. Predictive models were constructed using logistic regression, random forest, and support vector machine (SVM) algorithms.Results: Non-responders had elevated baseline interleukin-8 (IL8) and CD6 levels and reduced thymic stromal lymphopoietin (TSLP) compared to responders. ELISA confirmed differential expression of IL8, CD6, and TSLP, with CD6 showing the best diagnostic accuracy (AUC=0.800). The logistic regression model combining these markers achieved an AUC of 0.828 (95% CI: 0.701– 0.954), outperforming random forest (AUC=0.745) and SVM (AUC=0.775).Conclusion: Baseline plasma IL8, CD6, and TSLP are potential predictive biomarkers of long-term endoscopic response to UST in CD, providing a basis for personalized treatment strategies.Plain Language Summary: We analyzed baseline plasma from Crohn’s disease patients receiving ustekinumab and found that elevated levels of IL-8 and CD6, with reduced TSLP expression, predict poor response. Measuring these proteins may guide more personalized treatment decisions.Keywords: crohn disease, ustekinumab, biomarkers, proteomics