Appendix in ulcerative colitis pathogenesis and therapy: An updated narrative review

Table 1 Key clinical trials evaluating appendectomy in ulcerative colitis

Trial	Study design	Population (sample size)	Intervention	Comparison	Outcome measures	Adverse effects	Key findings	Clinical implication	Strengths	Limitation	Level of evidence
PASSION (2019)[31]	Prospective pilot study conducted at two European tertiary IBD centres (Netherlands and Ireland)	Adults (> 18 years) with steroid-dependent or therapy-refractory. UC who have failed medical management and require colectomy n = 30	Laparoscopic appendectomy + patient’s baseline medical therapy (tapered postoperatively in case of response)	No comparison group	Primary: Clinical response at 12 months. Secondary: Endoscopic remission and pathologic response at 12 months	No major postoperative complications, e.g., skin rash, postoperative abdominal tenderness	Clinical response in 12 (30%) at 12 months. 5 of these additionally showed endoscopic remission, 50% pathological response. Complete steroid withdrawal in all patients who had not yet had colectomies at 12 months	Proof-of-concept that the appendix contributes to disease activity and hence the potential of appendectomy for UC patients with appendiceal inflammation	Consecutive sampling strategy. Prospective study design. Correlation of clinical, endoscopic, and pathological responses → ↓ placebo effect contribution to results	Short follow-up duration. Small sample size	Level IV
ACCURE (2025)[32]	Multicenter (22 centres across the Netherlands, United Kingdom, and Ireland), randomized controlled superiority trial, utilizing an open-label, pragmatic design	Adults (≥ 18 years) with established UCs currently in remission and a medically treated flare within 12 months. n = 197 (n = 99 appendectomy; n = 98 control)	Laparoscopic appendectomy + patient’s baseline medical therapy	Patient’s baseline medical therapy	Primary: 12-month relapse rate. Secondary: Annual relapse frequency, time-to-first relapse, disease activity, colectomy rate, medication use, and health-related quality-of-life	11% in the appendectomy group vs 10% in the control group. Self-limiting postoperative abdominal pain (n = 3). Major adverse events (n = 2), e.g., internal hernia requiring laparotomy, intra-abdominal hematoma	Significantly lower 12-month relapse rate in the appendectomy group (36% vs 56%). Lower mean total Mayo score at 12 months (1.2 vs 1.8), less frequent initiation of biologics, superior control of bowel symptoms in the appendectomy group	Supports appendectomy for the maintenance of remission in UC patients	High-quality RCT (3/5 on the Jadad scale. International multicenter pragmatic design. → ↑ External validity. Robust computer-generated randomization and allocation concealment. Masked outcome assessment via a dedicated blinded critical event committee → ↓ observer bias	Short follow-up duration (12 months). Open-label design and possible placebo effect contribution. Possible chronological bias owing to long study duration (September 2012 to September 2022). Possible participation bias. Possible expectation bias with the publication of encouraging appendectomy studies	Level II
COSTA (2026)[33]	Multicentre, prospective interventional cohort study utilizing a patient-preference design across five hospitals in the Netherlands	Biologic-exposed patients ≥ 16 years with active UC and ≥ 1 instance of biologic therapy failure. n = 116 (modified intention-to-treat) (appendectomy n = 67; JAK-inhibitor therapy n = 49)	Appendectomy + patient’s baseline medical therapy (including advanced medical therapies, e.g., anti-TNFs, JAK-inhibitors)	JAK-inhibitor + patient’s basal medical therapy (EXCLUDING biologics which were stopped)	Primary: 12-month failure-free clinical remission rate. Secondary: Steroid-free remission rate; time-to-first remission; clinical response; endoscopic response; therapy failure rate; colectomy rate	No significant difference in AEs between groups (56.5% vs 60.0% in the JAK-inhibitor and appendectomy groups, respectively; P = 0.70). Low postoperative complication rate (4%); minor postsurgical complications (n = 3)	33% failure-free remission with appendicectomy; significantly superior to JAK inhibitors (12%) at 12 months. Consistently higher rates of steroid-free remission, clinical response, and endoscopic improvement/response. No significant difference in time-to-remission or overall therapy failure rates. Well-tolerated; 4% postoperative complication rate	Potential of appendectomy as a promising adjunct or alternative for induction of remission in biologic-refractory patients	Patient preference design → ↓ patient preference bias. Centralized, blinded endoscopic assessments → ↓ observer bias and interobserver variability. Multicenter design → ↑ External validity	Non-randomized with differences in baseline characteristics. High probability of selection bias. Non-standardized escalation of medical therapy. Relatively small sample size (though the study maintained adequate power)	Level III

IBD: Inflammatory bowel disease; UC: Ulcerative colitis; RCT: Randomized controlled trial; JAK: Janus kinases; TNF: Tumor necrosis factor; AEs: Adverse events.