Atay A, Ergul M, Ozturk O, Acun KC, Cagir Y, Durak MB, Yuksel I. Outcomes of 5-aminosalicylates withdrawal due to non-adherence in ulcerative colitis patients: A step toward evaluating intermittent therapy. World J Gastroenterol 2025; 31(30): 110112 [DOI: 10.3748/wjg.v31.i30.110112]
Corresponding Author of This Article
Ilhami Yuksel, MD, Professor, Department of Gastroenterology, Faculty of Medicine, Ankara Yildirim Beyazit University, İhsan Dogramaci Cad. Bilkent, Ankara 06800, Türkiye. yukselilhami@hotmail.com
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Retrospective Cohort Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Author contributions: Atay A and Yuksel I conceptualized, planned the design of the study, performed data analysis, interpreted the data, and drafted the manuscript; Atay A, Ergul M, Ozturk O, Acun KC, Cagir Y, Durak MB, and Yuksel I performed the data collection; All authors revised and approved the final version of the submitted manuscript to be submitted.
Institutional review board statement: This study was approved by the Ethics Committee of the Ankara Bilkent City Hospital (No. TABED 1-25-1090) and was conducted according to the Declaration of Helsinki.
Informed consent statement: Due to the retrospective nature of the study and use of de-identified data, informed consent was not obtained. This approach was reviewed and approved by the institutional ethics committee.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
STROBE statement: The authors have read the STROBE Statement—a checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-a checklist of items.
Data sharing statement: The technical appendix, statistical code, and dataset are available from the corresponding author at (yukselilhami@hotmail.com). Due to the retrospective nature of the study and use of de-identified data, informed consent was not obtained. This approach was reviewed and approved by the institutional ethics committee.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Ilhami Yuksel, MD, Professor, Department of Gastroenterology, Faculty of Medicine, Ankara Yildirim Beyazit University, İhsan Dogramaci Cad. Bilkent, Ankara 06800, Türkiye. yukselilhami@hotmail.com
Received: May 30, 2025 Revised: June 14, 2025 Accepted: July 18, 2025 Published online: August 14, 2025 Processing time: 69 Days and 15.9 Hours
Abstract
BACKGROUND
5-aminosalicylates (5-ASA) are the primary treatment for mild to moderate ulcerative colitis (UC). Maintenance therapy with 5-ASA has been shown to reduce both the risk of relapse and colorectal cancer.
AIM
To evaluate the outcomes of 5-ASA withdrawal due to non-adherence in UC patients while in remission on monotherapy.
METHODS
Adult patients with UC who were followed up between July 2019 and April 2025 were screened. Patients in remission receiving 5-ASA monotherapy who experienced treatment withdrawal due to non-adherence were included in this study.
RESULTS
Among 880 patients with UC, 30 (3.4%) had 5-ASA withdrawal due to non-adherence while in remission on monotherapy. Twelve patients (40%) had disease relapse after a median of 20 months. The rate of patients in remission was 89% in the first year, decreasing to 73% in the second year, and to 64% in the third year. There were no significant differences between patients with and without relapse in terms of demographics, disease extent, remission duration before 5-ASA withdrawal, previous medications, steroid dependence, 5-ASA formulation, baseline inflammatory markers, or partial and endoscopic Mayo scores. Most patients (75%) who experienced relapse were successfully treated with 5-ASA monotherapy, while one-fourth of them required corticosteroids. No patients required biologic agents, hospitalization, or surgical intervention.
CONCLUSION
Intermittent therapy may be safe and feasible for UC patients, especially those in long-term remission, with treatment interruption up to one year considered acceptable.
Core Tip: In this study, 5-aminosalicylate (5-ASA) withdrawal was observed in 3.4% of patients with ulcerative colitis (UC). Almost half of them developed a relapse. The majority of patients who experienced relapse were treated with 5-ASA monotherapy, while one-fourth of them required corticosteroids. No patients required biological agents, hospitalization, or surgery. Based on our long-term real-world data, intermittent therapy may represent a potentially safe and feasible strategy in terms of relapse risk in patients with UC. Notably, in patients who have sustained long-term clinical remission, a treatment interruption of up to one year may be considered safe.
Citation: Atay A, Ergul M, Ozturk O, Acun KC, Cagir Y, Durak MB, Yuksel I. Outcomes of 5-aminosalicylates withdrawal due to non-adherence in ulcerative colitis patients: A step toward evaluating intermittent therapy. World J Gastroenterol 2025; 31(30): 110112
5-aminosalicylates (5-ASA) are the primary treatment for mild to moderate ulcerative colitis (UC)[1,2]. These agents are generally safe and well tolerated[3]; however, topical 5-ASA therapy may be less tolerated and associated with lower adherence compared to oral therapy[4,5]. Maintenance therapy with 5-ASA has been shown to reduce both the risk of relapse and the likelihood of colorectal cancer[6-8], yet it also highlights that treatment withdrawal may still be considered in specific subgroups of patients with UC. While emerging evidence suggests that 5-ASA withdrawal may be safe in specific patient subgroups[9], treatment withdrawal decisions should always consider patient preferences. Withdrawal of 5-ASA in patients receiving monotherapy is associated with an increased risk of relapse. A randomized controlled trial showed that 5-ASA was significantly more effective than placebo in preventing relapse among UC patients in remission for 1-2 years[5,6,8,10]. However, in patients who had maintained remission for more than two years prior to withdrawal, the risk of relapse was comparable to those who continued treatment. Although long-term 5-ASA therapy is recommended for disease control and colorectal cancer prevention, current guidelines suggest that withdrawal may be considered for patients with limited disease extent, long-term remission, a history of only one disease flare, and no previous corticosteroid use[1]. Despite consensus regarding the optimal initiation of treatments in inflammatory bowel disease (IBD), uncertainty remains about the risks, benefits, and appropriate timing of treatment withdrawal during sustained remission. Evidence for the impact of 5-ASA withdrawal in UC patients is limited. The decision to withdrawal of treatment often leads to hesitation, particularly due to concerns about the difficulty of re-establishing remission with the same therapies and the possible loss of the chemopreventive effect against colorectal cancer. In our study, we hypothesized that in UC patients who have long-standing remission, 5-ASA withdrawal due to non-adherence would not lead to a significant increase in relapse rates over short-term follow-up. Therefore, we aimed to assess outcomes of treatment withdrawal in UC patients who were in remission on 5-ASA monotherapy. Given the limited research on this topic, our aim was to offer new insights into this underexplored area.
MATERIALS AND METHODS
Adult patients with UC who were followed up at our IBD clinic between July 2019 and February 2025 were screened. These patients were diagnosed with UC based on a comprehensive assessment including clinical symptoms, laboratory tests, imaging, endoscopy, and histopathological findings. Disease extensions were classified as proctitis, left-sided UC, or extensive UC according to the Montreal classification system[11]. Patients with UC who were followed in remission with 5-ASA monotherapy were evaluated. Remission status was assessed both clinically and endoscopically. Patients with treatment withdrawal due to patient non-adherence during remission were consecutively included in the study. Non-adherence was defined as patient-reported discontinuation of therapy without medical advice, based on data from longitudinal electronic medical records. The date of treatment withdrawal was initially obtained during the patient’s first visit following discontinuation and was subsequently re-confirmed at each follow-up visit. This information was simultaneously verified through the national prescription database, which provides a 10-year record of medical history. The absence of prescriptions after the reported withdrawal date served as confirmation, and the data were recorded accordingly. These records were retrieved from both our hospital’s electronic medical record system and a dedicated online medical database system specifically designed by our team to ensure uninterrupted patient follow-up and documentation. The main exclusion criteria were patients under 18 years of age, patients receiving continued 5-ASA treatment during remission, those who had undergone 5-ASA treatment withdrawal without being in remission, and patients who were receiving concomitant medications other than 5-ASA before treatment withdrawal. The study data were obtained from hospital records and an online database system used for the prospective follow-up of IBD patients. The age at diagnosis of UC, gender, smoking history, family history of IBD, presence of appendectomy, body mass index (BMI), total disease duration, follow-up time from 5-ASA withdrawal, remission duration before 5-ASA withdrawal, and presence of extraintestinal manifestation (EIM) were evaluated for the patients included in the study.
In addition, previous medical history, presence of steroid dependence, baseline (at the time of initial diagnosis) laboratory analysis [C-reactive protein (CRP), hemoglobin, and albumin], partial Mayo (pMayo) score, and endoscopic Mayo (eMayo) score were recorded. The time interval between 5-ASA withdrawal and relapse, and the duration of follow-up after relapse were analyzed. In patients who experienced a relapse, the treatment required to achieve remission, the duration of achieved remission, and the time from remission to relapse were also recorded. Clinical remission was defined as the presence of normal laboratory parameters (normal CRP, absence of anemia, and normal serum albumin levels) alongside a pMayo score of less than 2. The pMayo score included subscores for stool frequency, rectal bleeding, and the physician’s global assessment of disease activity. Endoscopic remission was evaluated using the eMayo subscore, whereby a score of 0 indicates normal mucosa; 1 indicates erythema, decreased vascular pattern, and mild friability; 2 indicates marked erythema, loss of vascular pattern, friability, and erosions; and 3 indicates spontaneous bleeding and ulcerations. An eMayo subscore of less than 2 was considered indicative of endoscopic remission. Relapse was defined by both clinical and endoscopic criteria. Clinical relapse was defined by the presence of abnormal laboratory parameters (elevated CRP, anemia, and low serum albumin levels) alongside a pMayo score ≥ 2. Endoscopic relapse was defined as an eMayo subscore > 2.
Statistical analysis
All statistical analyses were performed using IBM SPSS Statistics for Windows, Version 28.0 (IBM Corp., Armonk, NY, United States). The Shapiro-Wilk test was used to assess the normality of continuous variables. Continuous variables were presented as medians and interquartile ranges (IQRs) due to non-normal distributions, and categorical variables were expressed as frequencies and percentages. Comparisons between the relapse and non-relapse groups were conducted using the Mann-Whitney U test for continuous variables and the χ2 test or Fisher’s exact test for categorical variables, as appropriate. A P value < 0.05 was considered statistically significant. Kaplan-Meier survival analysis was performed to evaluate the trend of proportions of patients without relapse in UC patients who had 5-ASA withdrawal during remission.
RESULTS
Of the 880 patients with UC, 30 (3.4%) had 5-ASA withdrawal due to non-adherence while in remission on monotherapy (Supplementary Figure 1). Demographics, clinical and laboratory findings are summarized in Table 1. The median age of the patients was 31.0 years (IQR: 22.0-36.0 years), 13 (43.3%) were female, and the median BMI was 23.5 (IQR: 20.6-27.5). Seven patients (23.3%) were current smokers, and 8 (26.7%) had a history of smoking. Six (20.0%) patients had a family history of IBD. The median total disease duration was 175.0 months (IQR: 86.0-254.3 months), the median remission duration before 5-ASA withdrawal was 140.5 months (IQR: 20.3-192.3 months) and mean: 123.1 months, and the median follow-up period after 5-ASA withdrawal was 26.0 months (IQR: 16.8-65.0 months). The majority of patients (21, 70%) had left-sided UC, followed by 6 (20%) with proctitis and 3 (10%) with extensive UC. EIMs were present in 14 (46.7%) patients. The most commonly withdrawn 5-ASA formulation was tablets (25, 83.3%), followed by enemas (18, 60.0%), suppositories (6, 20.0%), and granules (2, 6.7%). In terms of laboratory parameters, the median baseline CRP levels were at or below the limit of detection in most patients. The median hemoglobin was 13.0 g/dL (IQR: 12.0-13.0 g/dL), and albumin was 4.0 g/dL (IQR: 4.0-4.2 g/dL).
Table 1 Demographic characteristics, clinical and laboratory findings of patients with 5-aminosalicylate withdrawal, n (%).
Characteristics
Total (n = 30)
Age at onset of IBD (years), median (IQR)
31.0 (22.0-36.0)
Female/male
13 (43.3)/17 (56.7)
Smoking status (current/ex/non-smokers)
7/8/15
Family history of IBD
6 (20.0)
BMI (kg/m2), median (IQR)
23.5 (20.6-27.5)
Total disease duration (months), median (IQR)
175.0 (86.0-254.3)
Duration of remission before 5-ASA withdrawal (months), median (IQR)
140.5 (20.3-192.3)
Follow-up time from 5-ASA withdrawal (months), median (IQR)
26.0 (16.8-65.0)
Disease extension
Proctitis
6 (20.0)
Left-sided UC
21 (70.0)
Extensive UC
3 (10.0)
Extra-intestinal manifestations
14 (46.7)
Prior medications
5-ASA tablet
25 (83.3)
5-ASA granule
2 (6.7)
5-ASA enema
28 (93.3)
5-ASA suppository
5 (16.7)
Sulfasalazine
1 (3.3)
Steroids
9 (30.0)
Thiopurine
3 (10.0)
Adalimumab
0 (0.0)
Infliximab
2 (6.7)
Vedolizumab
0 (0.0)
Ustekinumab
0 (0.0)
Steroid dependence
3 (10.0)
Withdrawal 5-ASA formula
5-ASA tablet
25 (83.3)
5-ASA granule
2 (6.7)
5-ASA enema
18 (60.0)
5-ASA suppository
6 (20.0)
Relapse
12 (40.0)
Baseline CRP (mg/L), median (IQR)
5.0 (5.0-5.0)
Baseline hemoglobin (g/dL), median (IQR)
13.0 (12.0-13.0)
Baseline albumin (g/dL), median (IQR)
4.0 (4.0-4.2)
Baseline eMayo subscore, median (IQR)
1.0 (1.0-1.3)
Baseline pMayo score, median (IQR)
5.0 (5.0-5.0)
The median baseline eMayo subscore was 1.0 (IQR: 1.0-1.3), and the median baseline pMayo was 5.0 (IQR: 5.0-5.0). Of the patients, 12 (40.0%) experienced disease relapse, whereas 18 (60.0%) maintained remission throughout the follow-up period. Comparisons of demographic, clinical, and laboratory characteristics between relapse and non-relapse groups are presented in Table 2. The median age at onset was comparable between the relapse (31.0 years, IQR: 21.5-34.8) and non-relapse (31.5 years, IQR: 22.0-37.8) groups (P = 0.545). The gender distribution was also statistically similar between groups, with a female-to-male ratio of 4:8 in the relapse group and 9:9 in the non-relapse group (P = 0.367). Smoking status, family history of IBD, appendectomy status, and BMI did not differ significantly between the groups. The total disease duration was slightly longer in the relapse group (median 193.5 months, IQR: 89.3-270.8) than in the non-relapse group (167.5 months, IQR: 69.5-237.5), but the difference was not statistically significant (P = 0.465). The duration of remission before 5-ASA withdrawal was also longer in the relapse group (152.0 months, IQR: 26.0-206.5) than the non-relapse group (122.0 months, IQR: 15.3-172.3), though it was not statistically significant (P = 0.391). The median follow-up duration after 5-ASA cessation was 26.0 months (IQR: 16.8-65.0) in the entire cohort, with no significant difference between relapse (23.5 months, IQR: 14.3-67.3) and non-relapse (29.0 months, IQR: 17.3-61.3) groups (P = 0.602).
Table 2 Comparison of demographic characteristics, clinical and laboratory findings between relapse and non-relapse groups, n (%).
Left-sided colitis was the most common subtype both in relapsing (7, 58.3%) and non-relapsing (14, 77.8%) patients, followed by proctitis (3, 25.0% vs 3, 16.7%), and extensive colitis (2, 16.7% vs 1, 5.6%) (Figure 1). There were no significant differences in disease extent between the relapse and non-relapse groups. The most prevalent 5-ASA formulations previously used were oral forms (83.3%) and enemas (60.0%) in the 30 patients. The use of 5-ASA granules, suppositories, and sulfasalazine was less frequent. Notably, steroid use was more common in the relapse group (50.0%) compared to the non-relapse group (16.7%), although this difference was not statistically significant (P = 0.102). Thiopurine and biologic therapies were rarely used. Steroid dependence was observed in three patients (10.0%) overall, with a slightly higher proportion in the relapse group (16.7%) than in the non-relapse group (5.6%). Baseline inflammatory markers and activity scores were comparable between the two groups. Median CRP levels were uniformly low across all patients (5.0 mg/L, IQR: 5.0-5.0 in the relapse group and 5.0 mg/L, IQR: 4.2-5.0 in the non-relapse group; P = 0.917). Hemoglobin and albumin levels were within normal ranges and similar between the groups. The eMayo subscore at baseline was mild in both groups (median score: 1.0), and pMayo scores were consistent (median score: 5.0) with no significant differences (Figure 2). All 12 patients in the relapse group experienced disease relapse at a median of 20.0 months (IQR: 12.3-52.3 months) following 5-ASA withdrawal. The majority of those were treated with 5-ASA formulations upon relapse (tablets in 75.0%, enemas in 50.0%, and suppositories in 16.7%), while three patients (25.0%) required corticosteroids, and one patient (8.3%) received thiopurine therapy. No patients required biologic agents or surgical interventions. Among the six patients who achieved both clinical and endoscopic remission after relapse, the median of the post-relapse remission period was 32.0 months (IQR: 6.3-59.3 months). The remaining six patients had not yet undergone confirmation of endoscopic remission, although clinical remission was achieved. Most of these patients were managed with 5-ASA monotherapy (75.0%), while others received combination therapy with corticosteroids (16.7%) or thiopurines (8.3%) (Table 3 and Figure 3). Figure 4 presents the Kaplan-Meier survival analysis for evaluating the trend of proportions of patients without relapse in UC patients who underwent 5-ASA withdrawal during remission. The rate of patients in remission was 89% in the first year, decreasing to 73% in the second year, and to 64% in the third year. Although the median follow-up period was 26.0 months (IQR: 16.8-65.0 months), relapse-free survival rates could be calculated over a period exceeding 10 years based on long-term follow-up data from a subset of patients. The rate of patients in remission gradually decreased over time and fell to 41% by the end of the 10th year (Figure 4).
Figure 1 A clustered bar chart showing the percentage of patients with proctitis, left-sided ulcerative colitis, and extensive ulcerative colitis in both relapse and non-relapse groups.
Black bars denote participants in the non-relapse group, whereas gray bars denote those in the relapse group. UC: Ulcerative colitis.
Figure 2 Boxplots comparing baseline inflammatory markers and activity scores between relapse and non-relapse groups.
The horizontal line within each box indicates the median, the box edges represent the interquartile range (IQR), and whiskers extend to 1.5 × IQR. Mild outliers (values beyond 1.5 × IQR), while extreme outliers (values beyond 3 × IQR). 1Mild outliers (values beyond 1.5 × IQR). 2Extreme outliers (values beyond 3 × IQR). CRP: C-reactive protein; eMayo: Endoscopic Mayo subscore; pMayo: Partial Mayo score.
Figure 4 Kaplan-Meier survival analysis for evaluating the trend of proportions of patients without relapse in ulcerative colitis patients who had 5-aminosalicylate withdrawal during remission.
The vertical drops in the curve represent relapse events, and the small vertical ticks indicate censored data points. The table below the X-axis shows the number and percentage of patients in remission at each time point.
Table 3 Subgroup analysis of results in patients with relapse, n (%).
Characteristics
Total (n = 12)
Time interval between 5-ASA withdrawal and relapse (months), median (IQR)
20.0 (12.3-52.3)
Duration time after relapse (months), median (IQR)
6.5 (0.0-46.5)
Treatment for remission in relapse
5-ASA tablet
9 (75.0)
5-ASA granule
1 (8.3)
5-ASA oral
10 (83.3)
5-ASA enema
6 (50.0)
5-ASA suppository
2 (16.7)
Sulfasalazine
0 (0.0)
Steroid
3 (25.0)
Thiopurine
1 (8.3)
Biologic agents
0 (0.0)
Surgery
0 (0.0)
DISCUSSION
5-ASA are the first-line treatment for mild to moderate UC and are generally considered safe and well tolerated[1-3]. Maintenance therapy with 5-ASA has been shown to reduce both the risk of relapse and the likelihood of colorectal cancer[6-8]. While emerging evidence suggests that 5-ASA withdrawal may be safe in specific patient subgroups[9], the decision for withdrawal of treatment often leads to hesitation, particularly due to concerns about the difficulty of re-establishing remission with the same therapies and the possible loss of the chemopreventive effect against colorectal cancer. Therefore, the number of patients who discontinued 5-ASA therapy is relatively small. Although increasing attention has been given to early and widespread treatment escalation, the outcomes of 5-ASA withdrawal in patients in remission remain underexplored. We evaluated real-world long-term outcomes of maintenance of remission with 5-ASA monotherapy and treatment withdrawal in a large cohort of UC patients. In this study, data that were recorded longitudinally at each visit were evaluated retrospectively, allowing for an objective assessment of outcomes. We observed 5-ASA withdrawal due to patient non-adherence in 30 patients (3.4%) in remission out of 880 UC patients, with disease relapse in 12 of them (40.0%). Demographic characteristics, baseline inflammatory markers, endoscopic scores, median follow-up duration after 5-ASA cessation, and disease extent were similar between the relapsing and non-relapsing groups. The median total disease duration was slightly longer in the relapse group (193 vs 167 months), and the duration of remission before 5-ASA withdrawal was also longer in the relapse group (152 vs 122 months), but these differences were not statistically significant. Remission was sustained in 89% of patients during the first year, declining to 73% in the second year and 64% in the third year. Remission was re-achieved with 5-ASA in 66% of the patients who experienced a relapse. The effectiveness of 5-ASA in maintaining remission is well established[1,7,12,13]. However, relatively few studies have evaluated the effects of treatment withdrawal. In a double-blind, randomized controlled trial, 112 UC patients who had been in remission for more than one year on 5-ASA or sulfasalazine were randomly assigned to receive either oral 5-ASA or placebo for 12 months. Among patients in disease remission for 1-2 years, 5-ASA was more effective as maintenance therapy, with a 12-month relapse rate of 23% in the 5-ASA group compared to 49% in the placebo group. In contrast, among the 51 patients who had been in remission for more than two years, no significant difference was observed in relapse rates between the 5-ASA and placebo groups (18% vs 26%, respectively)[10]. Similarly, Frias Gomes et al[14] reported that patients in remission for more than two years before treatment withdrawal had a relapse risk similar to those who continued therapy. In our study, relapse was observed in 11% of patients in the first year, 27% in the second year, and 36% in the third year following 5-ASA withdrawal. In our cohort, the median duration of remission before 5-ASA withdrawal was 140 months (IQR: 20.3-192.3 months), with disease relapse emerging at a median of 20.0 months after 5-ASA withdrawal. The relapse rate in our patients was considerably lower than previously reported results, possibly due to the markedly longer median remission duration before treatment cessation. These findings raise the question of whether intermittent treatment is possible in patients who have achieved long-term remission. If long-term maintenance therapy is unnecessary for specific patient groups, continued treatment could lead to unnecessary exposure to drug-related toxicity and significant healthcare costs (approximately 650 Pound to 760 Pound)[15]. Recent updates in UC guidelines acknowledge that intermittent treatment can be acceptable in selected patients with proctitis[1,7]. Consistently, our findings suggest that in patients with UC who have maintained long-term remission with 5-ASA monotherapy, the risk of relapse, particularly within the first year after treatment withdrawal, is low. Importantly, our results support this approach not only in patients with proctitis but also in those with complete remission regardless of disease extent. Therefore, intermittent therapy could be a reasonable strategy, especially given that indefinite follow-up without any treatment might not be realistic. At this stage, decisions about maintenance therapy should be guided by the drug’s efficacy in colorectal cancer prevention and the potential to re-induce remission following relapse, particularly when evaluating similar therapeutic agents. Current guidelines emphasize that 5-ASA therapy reduces the risk of colorectal cancer, and case-control studies have reported that regular and long-term use of 5-ASA significantly decreases this risk in patients with UC by up to 75%[5-7,16-18]. A 10-year cohort study showed that 31% of UC patients who discontinued or did not adhere to 5-ASA therapy developed colorectal cancer, compared to only 3% of those who maintained long-term treatment[19]. In our study, the median total disease duration was 175.0 months (range: 86.0-254.3 months), and the median follow-up time after 5-ASA withdrawal was 26.0 months (range: 16.8-65.0 months). During this period, the surveillance was conducted in accordance with the European Crohn’s and Colitis Organization guidelines[20]. No cases of dysplasia (low- or high-grade) or colorectal cancer were detected; however, this observation requires reevaluation in the long term. Given the known benefits of 5-ASA in both disease control and colorectal cancer prevention, current guidelines generally recommend long-term continuation of 5-ASA therapy, even in patients who are in clinical and endoscopic remission. The panel also considered that stopping treatment could be discussed in UC patients who have limited disease extent, such as proctosigmoiditis; have been in remission for several years; have a history of only a first or single disease flare; and have not required systemic corticosteroid therapy[1,7]. In addition, Lee et al[21] reported that relapse rates were higher among patients with left-sided or extensive colitis at diagnosis. Recent studies have also indicated that while most UC patients receive 5-ASA at some point during their disease course, those on 5-ASA monotherapy are at greater risk of relapse following treatment withdrawal. However, patients who have remained in remission for more than two years appear to have a similar risk of relapse regardless of whether they continue treatment. Accordingly, it has been suggested that safe withdrawal could be feasible in certain well-defined subgroups of patients[10,14]. In our study, we analyzed disease extent, remission duration before 5-ASA withdrawal, previous medications, presence of steroid dependence, 5-ASA withdrawal formulas, baseline inflammatory markers, pMayo score, and eMayo subscore data among relapsed and non-relapsed patient groups. Contrary to previous assumptions, if clinical and endoscopic complete remission is achieved, our study did not identify an increased risk of relapse associated with the initial disease extent, the number of attacks, and the history of steroid requirement. However, since the number of patients evaluated for this purpose was relatively low, as expected, further comprehensive multicenter studies are needed.
In the context of treatment withdrawal, there is insufficient data to address concerns regarding the difficulty of re-inducing remission with the same therapies. In our cohort, most patients who experienced a relapse were successfully treated with 5-ASA formulations upon relapse (oral tablets in 75.0%, enemas in 50.0%, and suppositories in 16.7%). Three patients (25.0%) required corticosteroids, and one (8.3%) was treated with a thiopurine. No patients required hospitalization, treatment with biologic agents, or surgical intervention. Based on these findings, the likelihood of regaining remission after relapse following treatment withdrawal appears favorable in our cohort; however, variability in relapse severity and response to re-treatment should be carefully considered in clinical decision-making. Our study has some limitations. First, this is a retrospective study conducted at a single institution. Second, the relatively low number of included patients was expected, as the 5-ASA withdrawal strategy is not widely implemented in clinical practice. Therefore, it is possible that we were unable to identify a safer, more specific patient subgroup for 5-ASA withdrawal. Based on post hoc power analysis, the current sample size (n = 30) provides 80% power to detect large effect sizes (w = 0.60 for χ2 tests and d = 0.97 for non-parametric comparisons). Therefore, the study may be underpowered to detect small-to-moderate differences between subgroups. In addition, unmeasured factors, such as diet, stress levels, or probiotic use, could not be controlled for and might have affected outcomes. Moreover, the limited sample size and relatively short median follow-up period restrict the study’s ability to draw firm conclusions, particularly regarding long-term outcomes and relapse predictors. Strengths of our study include the selection of a homogeneous patient population comprising individuals in both clinical and endoscopic remission who were receiving 5-ASA monotherapy from a large cohort, and the use of real-world data derived from a retrospective analysis of a prospective database.
CONCLUSION
In this study, 5-ASA withdrawal was observed in 3.4% of all patients with UC. Almost half of them developed a relapse. The majority of patients who experienced relapse were treated with 5-ASA monotherapy, while one-fourth of them required corticosteroids. No patients required biological agents, hospitalization, or surgical interventions. Based on our long-term real-world data, intermittent therapy may represent a potentially safe and feasible strategy in terms of relapse risk in patients with UC undergoing continued cancer surveillance. Notably, in patients who have sustained long-term clinical remission, a treatment interruption of up to one year may be considered safe. However, these findings should be interpreted with caution, as they may not be generalizable to all UC patients. Careful patient selection is crucial, taking into account disease phenotype, prior disease behavior, and relapse history. The heterogeneity of UC underscores the need for individualized clinical decision-making when considering 5-ASA withdrawal.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: Türkiye
Peer-review report’s classification
Scientific Quality: Grade B, Grade B, Grade B
Novelty: Grade B, Grade B, Grade C
Creativity or Innovation: Grade C, Grade C, Grade C
Scientific Significance: Grade B, Grade B, Grade B
P-Reviewer: Delgado-Miguel C; Yau TO S-Editor: Fan M L-Editor: A P-Editor: Zheng XM
Harbord M, Eliakim R, Bettenworth D, Karmiris K, Katsanos K, Kopylov U, Kucharzik T, Molnár T, Raine T, Sebastian S, de Sousa HT, Dignass A, Carbonnel F; European Crohn’s and Colitis Organisation [ECCO]. Third European Evidence-based Consensus on Diagnosis and Management of Ulcerative Colitis. Part 2: Current Management.J Crohns Colitis. 2017;11:769-784.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 938][Cited by in RCA: 873][Article Influence: 109.1][Reference Citation Analysis (0)]
Lamb CA, Kennedy NA, Raine T, Hendy PA, Smith PJ, Limdi JK, Hayee B, Lomer MCE, Parkes GC, Selinger C, Barrett KJ, Davies RJ, Bennett C, Gittens S, Dunlop MG, Faiz O, Fraser A, Garrick V, Johnston PD, Parkes M, Sanderson J, Terry H; IBD guidelines eDelphi consensus group, Gaya DR, Iqbal TH, Taylor SA, Smith M, Brookes M, Hansen R, Hawthorne AB. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults.Gut. 2019;68:s1-s106.
[RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)][Cited by in Crossref: 1402][Cited by in RCA: 1559][Article Influence: 259.8][Reference Citation Analysis (0)]
Doherty G, Katsanos KH, Burisch J, Allez M, Papamichael K, Stallmach A, Mao R, Berset IP, Gisbert JP, Sebastian S, Kierkus J, Lopetuso L, Szymanska E, Louis E. European Crohn's and Colitis Organisation Topical Review on Treatment Withdrawal ['Exit Strategies'] in Inflammatory Bowel Disease.J Crohns Colitis. 2018;12:17-31.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 165][Cited by in RCA: 144][Article Influence: 20.6][Reference Citation Analysis (0)]
Noda T, Kuwaki K, Machida M, Okumura Y, Nishioka Y, Myojin T, Imamura T. Persistence of newly prescribed 5-aminosalicylic acid in patients with ulcerative colitis: A nationwide comprehensive database study.PLoS One. 2024;19:e0316181.
[RCA] [PubMed] [DOI] [Full Text][Reference Citation Analysis (0)]
Bressler B, Marshall JK, Bernstein CN, Bitton A, Jones J, Leontiadis GI, Panaccione R, Steinhart AH, Tse F, Feagan B; Toronto Ulcerative Colitis Consensus Group. Clinical practice guidelines for the medical management of nonhospitalized ulcerative colitis: the Toronto consensus.Gastroenterology. 2015;148:1035-1058.e3.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 261][Cited by in RCA: 300][Article Influence: 30.0][Reference Citation Analysis (0)]
Magro F, Gionchetti P, Eliakim R, Ardizzone S, Armuzzi A, Barreiro-de Acosta M, Burisch J, Gecse KB, Hart AL, Hindryckx P, Langner C, Limdi JK, Pellino G, Zagórowicz E, Raine T, Harbord M, Rieder F; European Crohn’s and Colitis Organisation [ECCO]. Third European Evidence-based Consensus on Diagnosis and Management of Ulcerative Colitis. Part 1: Definitions, Diagnosis, Extra-intestinal Manifestations, Pregnancy, Cancer Surveillance, Surgery, and Ileo-anal Pouch Disorders.J Crohns Colitis. 2017;11:649-670.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 1446][Cited by in RCA: 1289][Article Influence: 161.1][Reference Citation Analysis (0)]
