Appendicectomy plus standard medical therapy versus standard medical therapy alone for maintenance of remission in ulcerative colitis (ACCURE): a pragmatic, open-label, international, randomised trial

Abstract

Background: The appendix might have an immunomodulatory role in ulcerative colitis. Appendicectomy has been suggested as a potentially therapeutic intervention to maintain remission in ulcerative colitis. We aimed to evaluate the clinical effectiveness of laparoscopic appendicectomy in maintaining remission in patients with ulcerative colitis.

Methods: We did a pragmatic, open-label, international, randomised controlled superiority trial in 22 centres across the Netherlands, Ireland, and the UK. Patients with established ulcerative colitis who were in remission but had been treated for disease relapse within the preceding 12 months were randomly assigned (1:1) to undergo appendicectomy plus continued maintenance medical therapy (intervention group) or to continue maintenance medical therapy alone (control group). Randomisation was done with a central, computer-generated allocation concealment, stratified by disease extent. Patients and treating physicians were unmasked to group allocation. The prespecified primary outcome was the proportion of patients with a disease relapse within 1 year, predefined as a total Mayo score of 5 or higher with an endoscopic subscore of 2 or 3, or, in absence of endoscopy, based on a centrally independent masked review by a critical event committee as an exacerbation of abdominal symptoms (eg, elevated stool frequency subscore of ≥1 point from baseline) with a rectal bleeding subscore of ≥1 or faecal calprotectin level above 150 μg/g or necessitating treatment intensification other than mesalazine. Analyses were done on an intention-to-treat principle. This trial is complete and was registered with the Netherlands Trial Register (NTR2883) and ISRCTN (ISRCTN60945764).

Findings: Between Sept 20, 2012, and Sept 21, 2022, 1386 patients were screened. 201 patients were randomly assigned to the appendicectomy group (n=101) or the control group (n=100). After exclusion of four patients due to eligibility violations (three had active disease and one received biological agents at time of randomisation), 99 patients in the appendicectomy group and 98 patients in the control group were included in the intention-to-treat analyses. The 1-year relapse rate was significantly lower in the appendicectomy group than in the control group (36 [36%] of 99 patients vs 55 [56%] of 98 patients; relative risk 0·65 [95% CI 0·47-0·89]; p=0·005; adjusted p=0·002). Adverse events occurred in 11 (11%) of 96 patients in the appendicectomy group and 10 (10%) of 101 patients in the control group. The most frequently reported adverse events were postoperative temporary self-limiting abdominal pain in the appendicectomy group (three [3%] patients) and skin rash in the control group (three [3%] patients). Two cases (2%) of low-grade appendiceal mucinous neoplasm were incidentally found in resected appendix specimens in the appendicectomy group. Serious adverse events occurred in two (2%) of 96 patients who underwent appendicectomy and none in the control group. There were no deaths.

Interpretation: Appendicectomy is superior to standard medical therapy alone in maintaining remission in patients with ulcerative colitis.

Funding: Fonds Nuts-Ohra and National Institute for Health Research Efficacy and Mechanism Evaluation.

Figure 1

Trial profile *Three patients were excluded because of active disease (two in appendicectomy group and one in the control group) and one patient in the control group was excluded due to receiving biological agents at the time of randomisation. †In the pragmatic intention-to-treat analysis, the same patients and allocation groups were used as in the intention-to-treat analysis, with the distinction in the relapse outcome of the re-baselined patients during the waiting period for appendicectomy.

Figure 2

Primary outcome result *Adjusted for age, sex, current smoking, disease extent, and weeks since most recent exacerbation.

Figure 3

Secondary outcome results (A) Kaplan–Meier survival analysis with log-rank testing. Kaplan–Meier plot with log-rank testing comparing the time-to-first-relapse following randomisation between the appendicectomy and control groups. Hazard rate is unadjusted for age, sex, current smoking, disease extent, and weeks since most recent exacerbation. Data at each timepoint are number at risk (number censored). (B) Health-related quality-of-life outcomes over time. *p<0·05 in generalised linear mixed models. EQ-5D-3L=EQ-5D 3-level. IBDQ=Inflammatory Bowel Disease Questionnaire.

Figure 4

Medication use (A) None. (B) Topical therapy, defined as rectal enemas or suppositories. (C) Oral mesalazine. (D) Systemic steroid, as oral corticosteroids (prednisone or equivalents or budesonide). (E) Immunomodulators (ie, azathioprine, methotrexate, thioguanine). (F) Biological agents, such as biological medication (anti-TNF, integrin antibody, or small molecules such as JAK inhibitors). In the generalised estimating equation, the baseline measurement was included as a fixed effect to adjust for initial differences between groups. Data for medication use were available for 97 patients in the appendicectomy group and 93 in the control group at 3 months; 89 and 90, respectively, at 6 months; 91 and 87, respectively, at 9 months; and 94 and 91, respectively, at 12 months.