Anti- tumor necrosis factor (TNF) agents are effective in preventing and treating postoperative recurrence (POR) in Crohn's disease (CD), while some patients have intolerance or fail treatment. Ustekinumab may offer an alternative, though data are limited. To compare the efficacy of anti-TNF agents with ustekinumab for preventing and treating POR in CD. Patients who initiated anti-TNF agents or ustekinumab within three months after surgery for POR prevention or after ileocolonoscopy with Rutgeerts score >= i2 for POR treatment were included. Endoscopic and clinical outcomes were evaluated. For preventing POR, 68 patients received anti-TNF agents and 34 received ustekinumab, showing no significant differences in endoscopic POR (p = 0.777). Ustekinumab had a lower rate of clinical POR (p = 0.004) and biological therapy discontinuation (p < 0.001). For treating POR, 35 received anti-TNF agents and 27 received ustekinumab, with no significant differences in endoscopic improvement (p = 0.632) or remission (p = 0.285). Ustekinumab showed a higher clinical treatment success (p = 0.004). Among 12 patients switching to ustekinumab after anti-TNF failure, 41.7% showed endoscopic remission, and 83.3% achieved clinical treatment success. Ustekinumab has better clinical outcomes and treatment persistence than anti-TNF agents in preventing and treating endoscopic POR in CD.

BackgroundCytotoxic T-Lymphocyte-Associated Protein 4 (CTLA4) haploinsufficiency is a rare monogenic immunodysregulatory disorder that can affect multiple organ systems, leading to a combination of autoimmunity, immunodeficiency, and lymphoproliferation. It is caused by heterozygous germline mutations of CTLA4, yet the structure-function relationships underlying individual pathogenic variants remain incompletely understood.MethodsWe performed whole-exome sequencing on a patient with adolescent-onset autoimmune enteropathy, early-onset gastric malignancy and multisystem comorbidities, who was initially misdiagnosed with Crohn’s disease and refractory to multiple biologics. Functional assays assessed CTLA4 dimerization and CD80/CD86 binding capacity. Peripheral blood immunophenotyping was conducted using CyTOF and flow cytometry. Intestinal histopathology was evaluated by immunohistochemistry. The patient subsequently received targeted therapy with abatacept.ResultsA novel heterozygous missense variant in CTLA4 (c.167T>G, p.Phe56Cys) was identified. Functional assays demonstrated that this variant impairs CTLA4 protein dimerization and its binding capacity to CD80/CD86, establishing loss-of-function as the molecular basis of pathogenicity. Comprehensive peripheral blood immunophenotyping by CyTOF revealed a broad adaptive immune dysregulation landscape, characterized by depletion of regulatory T cells (Tregs), γδ T cells, and CD161+ cytotoxic-like CD8+ T cells. Flow cytometry confirmed reduction in CD4+CD25+Foxp3+ Treg cells along with decreased CTLA4 expression. Intestinal histopathology showed crypt apoptosis with T cell-predominant infiltration, distinct from classic inflammatory bowel disease. Notably, targeted therapy with abatacept partially restored Treg frequency and alleviated clinical symptoms.ConclusionThese findings identify p.Phe56Cys as a novel loss-of-function CTLA4 variant that disrupts protein dimerization and ligand binding, expanding the mechanistic understanding of CTLA4 haploinsufficiency and supporting genetic screening in patients with refractory autoimmune enteropathy and early-onset gastric malignancy.

Crohn’s disease (CD) exhibits substantial heterogeneity in disease behavior and therapeutic outcomes across distinct disease locations. Specific alterations in the gut microbiota and metabolites may drive this variation. This review aims to characterize the distinctive microbial and metabolic signatures across CD phenotypes based on disease location. Electronic databases were searched from inception to December 2025 for studies that observed alterations in gut microbiota and metabolites in CD patients with different disease locations. Forty-eight studies including 3,577 CD patients and 2,916 healthy controls (HCs) were analyzed. Ileal Crohn’s disease (ICD) was characterized by significant dysbiosis compared with HCs, featuring enrichment of Enterobacteriaceae (especially adherent-invasive Escherichia coli [AIEC]), Fusobacterium and Shigella, alongside depletion of Faecalibacterium prausnitzii, Roseburia and Coprococcus. Patients with colonic Crohn’s disease (CCD) exhibited increased levels of Proteobacteria, pro-inflammatory families (Actinomycetaceae, Micrococcaceae) and opportunistic pathogens (Streptococcus, Klebsiella). In contrast, a decrease in short-chain fatty acid (SCFA)-producing families (Lachnospiraceae, Ruminococcaceae) and F. prausnitzii was observed in CCD. Ileocolonic Crohn’s disease (ICCD) displayed features combining ICD and CCD elements, with specific depletion in Alistipes communis and enrichment of Shigella flexneri. More pro-inflammatory bacteria were observed in ICD compared with CCD. In terms of metabolic alterations, ICD showed impaired enterohepatic bile acid circulation with excessive fecal loss of conjugated bile acids, while CCD exhibited defective conversion of primary to secondary bile acids. ICCD exhibited both impaired ileal reabsorption and defective colonic transformation. Our results identified disease location-specific alterations in the microbiome and metabolome of CD, which might be associated with the clinical manifestations and prognosis of different phenotypes.

BACKGROUND:Crohn disease (CD) is a chronic, recurrent inflammatory bowel disease. Mesenchymal stem cell-derived exosomes (MSC-Exos) have emerged as promising cell-free treatments for CD. OBJECTIVE:In this study we aimed to investigate the therapeutic effect and potential mechanisms of MSC-Exos derived from induced pluripotent stem cells (iPSCs) (iPSC-MSC-Exos) in patients with colitis. METHODS:iPSC-MSC-Exos were administered intraperitoneally to mice with trinitrobenzene sulfonic acid (TNBS)-induced colitis. The colonic stem cell markers Lgr5 and Bmi1, and the proliferation marker Ki-67 were assessed by immunofluorescence. Lamina propria mononuclear cells (LPMCs) were isolated from the mouse colons and analyzed by flow cytometry. Furthermore, microarray analysis was performed to identify the differential expression of micro RNAs (miRNAs) in the iPSC-MSC-Exos. iPSC-MSC-Exos with micro RNA (miR)-34a-5p overexpression (Exo-OE) or knockdown (Exo-KD) were used to treat colitis in the mice. The candidate targets of miR-34a-5p and its downstream signaling pathways were confirmed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blotting. RESULTS:The iPSC-MSC-Exos migrated to the inflamed colon and protected the colon stem cells against inflammatory damage, promoted epithelial cell proliferation, and decreased the infiltration of proinflammatory Th1/9/17, CD4 +  tumor necrosis factor alpha (TNF-α)+, and macrophage cells while increasing anti-inflammatory T-regulatory (Treg) and B-regulatory (Breg) cells to alleviate TNBS-induced colitis in the mice. The therapeutic effect was sustained for 7 days after a single injection. MiR-34a-5p Exo-OE magnified this effect, whereas Exo-KD abolished it. The iPSC-MSC-Exos also inhibited the proliferation and migration of CD4 + LPMCs isolated from patients with CD. The miR-34a-5p expression was significantly elevated in the iPSC-MSC-Exos, which inhibited PPP2R3A expression by directly targeting its 3' untranslated region (3'-UTR). MiR-34a-5p Exo-OE significantly decreased the expression of PPP2R3A while increasing the expression of the Wingless-related integration site (Wnt) signaling ligands of β-catenin (Wnt/β-catenin signaling) and CD44. CONCLUSIONS:iPSC-MSC-Exos ameliorated colitis and promoted mucosal healing in a TNBS-induced CD-like model by activating Wnt/β-catenin signaling via miR-34a-5p, which targets PPP2R3A.

BACKGROUND:While clinical trials have demonstrated that approximately 50% of patients with Crohn's disease (CD) maintain clinical remission at 1 year with infliximab (IFX), the outcomes of long-term IFX treatment in CD are still under scrutiny. RESEARCH DESIGN AND METHODS:This retrospective cohort study analyzed 113 patients with CD from September 2010 to July 2025 to evaluate adherence and clinical remission rates, as well as to identify factors associated with treatment adherence. RESULTS:The median duration of IFX treatment was 61.7 months. At the 72-month follow-up (M72), patients were categorized into M72-remission (44.2%) and M72-non-remission (55.8%) groups. The M72-remission group had a significantly higher baseline Crohn's disease activity index score than the M72-non-remission group (p = 0.003). However, this difference was no longer significant at the 72-month follow-up (p = 0.254). At the final follow-up, 67.3% of patients continued to receive IFX treatment. Both the adherence rate to IFX (p = 0.012) and the clinical remission rate (p = 0.030) were significantly higher in patients with no surgery compared to those with surgery prior to IFX treatment. CONCLUSIONS:Early clinical remission was not associated with the adherence to IFX treatment. Previous surgery may be an independent risk factor for long-term IFX treatment failure.

BACKGROUND:Crohn disease (CD) is frequently complicated by intestinal strictures, which require early recognition and management. This study aimed to identify biomarkers associated with CD-related strictures by use of serum and intestinal proteomics and to develop diagnostic and predictive models for potential clinical application. METHODS:Serum samples from treatment-naive CD patients and paired intestinal samples from stricturing intestine were subjected to proteomic analysis. Machine learning approaches were employed to select stricture-related biomarkers and develop models. The candidate protein was validated using external cohorts and molecular experiments. RESULTS:The discovery cohort included 62 patients. A diagnostic model for intestinal stricture was developed using serum levels of 5 proteins from 30 nonstricturing, nonpenetrating (B1) phenotype and 20 stricturing (B2) phenotype patients, achieving an area under the curve of 0.754. A predictive model for stricture progression, based on another set of 5 proteins in 10 B1 progressors, achieved an AUC of 0.947 internally. Serum enzyme-linked immunoassay (ELISA) validation in the First Affiliated Hospital of Sun Yat-sen University (FAH-SYSU) and Sir Run Run Shaw Hospital (SRRSH) cohorts (n = 62) confirmed elevated glypican-6 (GPC6) levels in the stricturing (B2) group, with a similar trend observed in intestinal tissue in the progression group of the RISK cohort (n = 237). Single-cell transcriptomic analysis and immunofluorescence staining further confirmed higher GPC6 expression and protein levels in the fibrostenotic mucosa and submucosa, particularly in fibroblasts. CONCLUSIONS:We developed serum-based diagnostic and predictive models for intestinal strictures in CD, which may be suitable for clinical use once externally adequately validated. GPC6 emerged as a candidate biomarker closely associated with intestinal fibrosis, offering promising implications for its diagnosis and prognosis.

BACKGROUND:Although triple therapy plus bismuth (TTPB), comprising a proton pump inhibitor (PPI), two antibiotics, and bismuth, is widely used to eradicate Helicobacter pylori (H. pylori), eradication rates have been suboptimal. Potassium-competitive acid blockers (P-CABs) offer stronger and more stable gastric acid inhibition compared to PPIs. This study aimed to compare the efficacy, safety, and compliance of tegoprazan-based TTPB (TACB) vs. esomeprazole-based TTPB (EACB) in treatment-naïve patients with H. pylori infection. METHODS:In this nationwide, multicenter, double-blind, double-dummy, randomized controlled trial conducted from October 2022 to September 2023 across 41 centers in China, 561 eligible patients with H. pylori infection were randomized (1:1) to receive either TACB (tegoprazan 50 mg, amoxicillin 1000 mg, clarithromycin 500 mg, and bismuth 220 mg) or EACB (esomeprazole 20 mg, amoxicillin 1000 mg, clarithromycin 500 mg, and bismuth 220 mg), all administered twice daily for 14 days. H. pylori eradication was assessed using the 13C-urea breath test at 4-8 weeks post-treatment. The primary endpoint was eradication rate based on the full analysis set (FAS). Statistical analysis included the chi-squared tests, with a predefined non-inferiority margin of -10%. RESULTS:In the FAS population, eradication rates were 93.5% (95% confidence interval [CI]: 89.9-96.1%) in the TACB group and 86.4% (95% CI: 81.9-90.2%) in the EACB group. The between-group difference was 7.0% (95% CI: 2.1-12.0%), indicating that tegoprazan-based TTPB was non-inferior to esomeprazole-based TTPB. Furthermore, superiority tests found a significantly higher eradication rate in tegoprazan group compared with esomeprazole group (P = 0.006). Similar results were observed in the per-protocol set. The incidence of treatment-emergent adverse events was comparable between groups (75.5% in TACB vs. 73.4% in EACB), with most events being mild and transient. Compliance was high in both groups (98.4% vs. 98.8%). CONCLUSION:TACB was non-inferior to EACB in H. pylori eradication efficacy, with similar safety and compliance profiles in Chinese treatment-naïve patients. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT05577468.

Metastatic liver tumor burden (LTB) is a prognostic factor affecting the survival of gastroenteropancreatic neuroendocrine tumors (GEP-NETs), but evaluation of the LTB usually depends on radiologic and functional imaging. This study aimed to develop a clinical model based on easily accessible clinicopathological markers to predict LTB level in GEP-NET patients. LTB was quantified based on 68Ga-DOTANOC PET/CT scan. The optimal cut-off value for high and low-LTB was determined based on our previous study. Serum levels of liver enzymes and tumor biomarkers were obtained within one week before PET/CT scan. The whole dataset was divided into training set and validation set. LASSO regression method was used to select predictors, and multivariate logistic regression was used to develop a clinical model which was further visualized by constructing a nomogram. Area under the curve (AUC) was applied to assess the accuracy of the constructed model. We retrospectively enrolled 200 patients with well-differentiated GEP-NETs. Ki-67 index, GGT (gamma-glutamyltransferase), LDH (lactate dehydrogenase), and NSE (neuron-specific enolase) were selected through the LASSO regression method, and a nomogram was built based on these variables. The predictive model yielded an AUC of 0.785 (95

Histological remission has emerged as a promising target that may improve long-term outcomes in patients with ulcerative colitis (UC). The aim of this study was to investigate correlations between clinical, endoscopic, and histological remissions and the predictive value of histological remission on long-term outcomes in patients with UC receiving conventional therapy. A retrospective study was conducted involving 183 patients with UC who underwent histological assessment between August 2004 and May 2018. Concordance among clinical, endoscopic, and histological remissions was evaluated using Fleiss kappa statistics. Cox multivariate regression analysis was performed to identify independent factors associated with long-term outcomes, including corticosteroid use, biologics requirements, hospitalization, and composite outcome of disease progression. At baseline, 84.7

Monogenic errors of immunity can present with inflammatory bowel disease (IBD)-like enteropathy. We describe an adolescent with IBD- and Behçet's-like phenotype, resulting from an intronic, loss of function mutation (c.248-7G > A) in ELF4, an X-linked transcription factor executing multiple biological functions. The mutation causes abnormal splicing and decreased mRNA expression and impairs ELF4 protein expression in the blood and colon. Functionally, the mutation results in loss of ELF4 transcriptional activity, and transcriptionally induces auto-inflammatory responses in the patient's peripheral blood mononuclear cells, which promote secretion of the pro-inflammatory cytokine interleukin-6 upon lipopolysaccharide stimulation. Single-cell transcriptional profiling of inflamed colonic biopsy specimens from the patient delineates a comprehensive landscape of mucosal innate and adaptive immune dysregulation. This analysis not only uncovers inflammatory signatures reminiscent of Crohn's disease but also demonstrates heightened angiogenic chemokine responses and enhanced chemotactic activity in innate immune cells. These results demonstrate that a new ELF4 loss-of-function intronic mutation predisposes to an intestinal autoinflammatory disorder.

Objectives Immune-driven inflammatory angiogenesis is a crucial component in the pathogenesis of inflammatory bowel disease (IBD). Nevertheless, the underlying mechanisms are still poorly understood. This study aims to investigate the role of Transglutaminase 2 (TGM2) in inflammatory angiogenesis in IBD and its potential as a therapeutic target and biomarker. Methods We performed an RNA-seq analysis integrated single-cell transcriptomic profiling on IBD biopsies to identify dysregulated genes. Additionally, we explored TGM2 contribution to angiogenesis and colitis under in vitro and in vivo conditions in Tgm2 knockout mouse and human intestinal microvascular endothelial cells (HIMECs). Serum TGM2 levels were measured by Enzyme-Linked Immunosorbent Assay. Results TGM2 expression was significantly upregulated in intestinal endothelial cells of IBD patients and colitis models. Tgm2 knockout and its inhibitor significantly attenuated intestinal colitis and angiogenesis in mice. In vitro, knockdown of TGM2 significantly suppressed tube formation, migration, and invasion of HIMECs. Mechanistically, inflammation-induced STAT1 activation promoted TGM2 expression, which subsequently interacted with vascular endothelial growth factor receptor 2 (VEGFR2) to drive its phosphorylation (Tyr1059, Tyr1214) and inflammatory angiogenesis. In patients of Crohn’s Disease, serum TGM2 concentrations exhibited high diagnostic accuracy (AUC = 0.862) for assessing endoscopic activity. Conclusion Our findings underscore the critical role of STAT1-TGM2-VEGFR2 axis in regulating angiogenesis during intestinal inflammation, suggesting that targeting TGM2 as a viable therapeutic candidate for vascular remodeling in chronic intestinal inflammation.

Background:Pancreatic angiosarcoma is a rare and highly aggressive tumor originating from lymphatic or vascular endothelial cells, with poor prognosis and few effective treatments. In this study, we aimed to characterize the tumor ecosystem of metastatic pancreatic angiosarcoma, along with its potential treatment strategies. Methods:Single-cell RNA-sequencing and bioinformatics analysis were performed on samples obtained from one patient, including at total of 16,841 cells from pancreatic angiosarcoma liver metastasis and adjacent normal liver tissue. Results:Pancreatic angiosarcoma cells exhibited marked upregulation of nuclear factor kappa-B (NF-κB), hypoxia-inducible factor 1 (HIF-1), and myelocytomatosis oncogene (MYC) proto-oncogene signaling pathways, while presenting limited upregulation of actionable therapeutic targets except for cyclin-dependent kinase 4 (CDK4) and epidermal growth factor receptor. Several immune checkpoint genes, including cytotoxic T-lymphocyte-associated protein 4 (CTLA4), lymphocyte-activation gene 3 (LAG3), programmed cell death protein 1 (PDCD1), and cluster of differentiation 86 (CD86), were upregulated in tumor-infiltrating T cells, natural killer (NK) cells, and myeloid cells. Furthermore, intercellular interaction profiling demonstrated enhanced activity of the programmed death-ligand 1 (PD-L1) and CD86 signaling pathways within the tumor microenvironment. The gene-set scores of T/NK-cell exhaustion, regulatory T cell, and macrophage angiogenesis were significantly higher in tumor tissues compared with adjacent normal tissues. However, the phagocytosis scores of macrophages within the tumor-infiltrating region were significantly lower than those in the adjacent normal tissues. Conclusions:Our findings outlined an immunosuppressive and angiogenic tumor ecosystem in pancreatic angiosarcoma liver metastasis, suggesting that pancreatic angiosarcoma may be insensitive to most targeted therapies. Conversely, immunotherapies targeting LAG3, PD-L1, and CD86 (e.g. isatuximab, Opdualag, and abatacept) and anti-angiogenic agents may be therapeutically effective and worthy of subsequent exploration.

BACKGROUND/AIMS:Ustekinumab (UST) and infliximab (IFX) are both effective in the treatment of perianal fistulizing Crohn's disease (CD), but limited research has focused on comparing the efficacy of UST versus IFX in this field. This study aimed to compare the effectiveness of UST or IFX in treating perianal fistula of CD patients naive to biological agents in a real-world setting. METHODS:A retrospective cohort study included patients with perianal fistulizing CD treated with UST or IFX was conducted to evaluate the rates of luminal and perianal fistula response and remission at 6 months after treatment. RESULTS:Ninety-seven patients (49 UST and 48 IFX) were enrolled. Compared to IFX, UST exhibited significantly higher rates of treatment success (89.8% vs. 50.0%, P< 0.001) and intestinal clinical response (85.7% vs. 68.8%, P= 0.048), but no significant differences in fistula remission, fistula response, fistula closure, intestinal clinical remission, endoscopic remission and endoscopic response was observed. Furthermore, multivariate analyses demonstrated complexity of fistula was conversely associated with fistula remission between the UST and IFX groups. Finally, the rates of disease relapse and operation in the IFX group were higher as compared to the UST group during follow-up. CONCLUSIONS:UST may serve as a promising alternative to IFX for the treatment of perianal fistulizing CD.

OBJECTIVES:To develop a nomogram with easily available parameters to predict the risk of Crohn's disease (CD)-related bowel resection in patients with newly diagnosed CD. METHODS:We performed a retrospective cohort study by recruiting patients with newly diagnosed CD between 2005 and 2022. The patients were divided into the training and internal test sets in a 7:3 ratio. Adjusted multivariate Cox regression and least absolute shrinkage and selection operator analyses were used for feature selection. A nomogram was developed and evaluated using 10-fold cross-validation. RESULTS:Altogether 490 patients were included, among whom 67 (13.7%) received CD-related bowel resection during a median follow-up of 45.2 months. Stricturing or penetrating behavior, perianal involvement, and higher C-reactive protein (CRP) were independently associated with a higher risk of CD-related bowel resection, while higher white blood cell (WBC) and lymphocyte levels and hemoglobin levels were protective factors. The nomogram including disease behavior, hemoglobin, CRP, and lymphocyte and WBC counts yielded a C-statistic of 0.80 (95% confidence interval [CI] 0.74-0.86) in 10-fold cross-validation of the training set. Using the internal test set, the robust performance was verified with C-statistic, calibration slope, and calibration-in-the-large of 0.80 (95% CI 0.70-0.89), 1.10 (95% CI 0.61-1.56), and 0.28 (95% CI -0.17 to 0.67). Decision curve analyses indicated its potential clinical utility. CONCLUSION:The nomogram integrating disease behavior and laboratory data might be a promising approach for early risk stratification of CD-related bowel resection, hence facilitating personalized treatment for newly diagnosed CD.

Objective: To determine the impact of trans-arterial embolization (TAE) on overall survival (OS) in patients with liver metastases from gastroenteropancreatic neuroendocrine tumors (LM-GEP-NETs) and to identify factors that may influence tumor response to TAE treatment. Methods: This study included patients with histologically and radiologically confirmed LM-GEP-NETs who received TAE treatment at The First Affiliated Hospital, Sun Yat-sen University, between November 2016 and January 2023. Imaging responses were assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and modified RECIST (mRECIST) criteria. Tumor response was defined as complete or partial remission. Results: In total, 267 patients with LM-GEP-NETs were included. Patients with liver tumor burdens <25%, 25–50%, and ≥50% had progressively worse OS (p < 0.005). According to the RECIST criteria, 65.9% of patients exhibited tumor responses. Using the mRECIST criteria, 77.5% of patients showed tumor responses. Survival analyses with log-rank tests indicated that patients with tumor responses assessed using either the RECIST or mRECIST criteria had significantly better OS (p = 0.015 and p = 0.023, respectively). Further logistic regression analyses showed that early TAE (within 4 months after diagnosis of liver metastases) was associated with tumor responses assessed using RECIST or mRECIST. These results were further verified using propensity score matching and inverse probability treatment weighting adjusted datasets. Conclusions: A higher liver tumor burden was associated with poorer OS in patients with LM-GEP-NETs. Tumor response after TAE indicates survival benefits. Early TAE (within 4 months of diagnosis) was associated with better treatment responses.

Intestinal stricture remains one of the most challenging complications in Crohn's disease, and its underlying mechanisms are poorly understood. Accumulating evidence suggests that gut microbiota is significantly altered in stenotic intestines and may play a key role in the development of fibrogenesis in Crohn's disease. Additionally, the presence of hypertrophic mesenteric adipose tissue, also known as creeping fat, is closely correlated with intestinal stricture and fibrosis. Recent findings have revealed that bacterial translocation to creeping fat might exacerbate colitis and promote intestinal fibrosis. However, there is still a gap in determining whether gut microbiota links the formation of creeping fat to intestinal fibrosis. Hence, this review aims to summarize the known microbial influences on intestinal fibrosis, describes the microbial characteristics of creeping fat in Crohn's disease, and discusses the crosstalk between creeping fat-associated dysbiosis and the development of intestinal fibrosis.

Objective Serum amyloid A (SAA) was found to be positively correlated with the activity of Crohn’s disease (CD); however, its prognostic value remains uncertain. Here, we examined its predictive ability in newly diagnosed CD and explored genetic association.Methods This retrospective cohort study included patients newly diagnosed as CD at the First Affiliated Hospital of Sun Yat-sen University between June 2010 and March 2022. We employed receiver operating characteristic curve, Cox proportional hazard regression models and restricted cubic splines to investigate the prognostic performance of SAA for surgery and disease progression. To assess possible causality, a two-sample Mendelian randomisation (MR) of published genome-wide association study data was conducted.Results During 2187.6 person-years (median age, 28 years, 72.4% male), 87 surgery and 153 disease progression events were documented. A 100-unit increment in SAA level generated 14% higher risk for surgery (adjusted HR (95% CI): 1.14 (1.05–1.23), p=0.001) and 12% for disease progression (1.12 (1.05–1.19), p<0.001). Baseline SAA level ≥89.2 mg/L led to significantly elevated risks for surgery (2.08 (1.31–3.28), p=0.002) and disease progression (1.72 (1.22–2.41), p=0.002). Such associations were assessed as linear. Adding SAA into a scheduled model significantly improved its predictive performances for surgery and disease progression (p for net reclassification indexes and integrated discrimination indexes <0.001). Unfortunately, no genetic causality between SAA and CD was observed in MR analysis. Sensitivity analyses showed robust results.Conclusion Although causality was not found, baseline SAA level was an independent predictor of surgery and disease progression in newly diagnosed CD, and had additive benefit to existing prediction models.