Withdrawal of TNF Antagonists in Patients with Inflammatory Bowel Disease in Remission: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Withdrawal of TNF Antagonists in Patients with Inflammatory Bowel Disease in Remission: A Systematic Review and Meta-analysis of Randomized Controlled Trials | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Withdrawal of TNF Antagonists in Patients with Inflammatory Bowel Disease in Remission: A Systematic Review and Meta-analysis of Randomized Controlled Trials Ahmed Adekunle Owolabi, Iqra Qazi, Nadia Ahmed, Mariam Amro Alsayed, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7842211/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Dec, 2025 Read the published version in International Journal of Colorectal Disease → Version 1 posted 6 You are reading this latest preprint version Abstract Background Tumor necrosis factor (TNF) antagonists are central to the management of inflammatory bowel disease (IBD), but concerns regarding long-term safety, infection risk, and costs have prompted interest in treatment de-escalation. Whether discontinuing TNF therapy in patients with sustained remission is safe remains uncertain. Methods We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing TNF antagonist withdrawal with continuation in IBD patients in sustained remission. Databases including MEDLINE, Embase, CENTRAL, and ClinicalTrials.gov were searched through July 2025. Eligible trials enrolled adults with Crohn’s disease or ulcerative colitis in clinical remission. Primary outcomes were relapse risk and sustained remission. Data were pooled using a random-effects model. Results Four RCTs comprising 485 patients were included. TNF antagonist withdrawal was associated with a significantly higher risk of relapse compared with continuation (RR: 3.00, 95% CI: 1.47–6.11). Time to relapse was also shorter in the withdrawal group (HR: 5.34, 95% CI: 2.05–13.92). Sustained clinical remission did not differ significantly between groups (RR: 0.83, 95% CI: 0.55–1.27). Withdrawal reduced infection risk (RR: 0.47, 95% CI: 0.25–0.90), while rates of gastrointestinal and serious adverse events were comparable. Conclusions Discontinuation of TNF antagonists in IBD patients in remission substantially increases the risk and accelerates the timing of relapse, though it lowers infection risk. Careful patient selection and close monitoring are essential if withdrawal is considered. Inflammatory Bowel Disease Tumor Necrosis Factor-alpha Antagonists and Inhibitors Meta-Analysis Figures Figure 1 Figure 2 Figure 3 1. INTRODUCTION The early advent of tumor necrosis factor (TNF) antagonists has significantly impacted the management of inflammatory bowel disease (IBD). These agents effectively control the progressive nature of IBD, enabling many patients to achieve remission while reducing the need for invasive interventions and hospitalizations [ 1 – 3 ]. Combination therapy with anti-TNF agents and immunomodulators (IMMs) has been proven to be effective in inducing and maintaining clinical and endoscopic remission, especially in patients with Crohn’s disease (CD) [ 4 ]. Unfortunately, prolonged combination therapy can be concerning regarding long-term safety risks, infections, and considerable costs [ 5 , 6 ]. Consequently, the discontinuation of IMM or the anti-TNF agents in IBD patients who achieved a sustained clinical remission has become an essential question in clinical practice. While IMM withdrawal has not consistently shown an increase in relapse rates, several randomized controlled trials (RCTs) suggest that anti-TNF withdrawal could be associated with significantly higher relapse rates [ 7 , 8 ]. Studies show a statistically significant relapse rate of 31.5% at 1–2 years following anti-TNF withdrawal, compared with 12% among those who continued combination therapy [ 7 – 9 ]. However, some studies have shown that withdrawal of anti-TNF agents does not significantly impact the relapse rates in patients with IBD [ 10 ]. Despite the inconsistent heterogeneous data, discontinuation of anti-TNF therapy remains a potential strategy for certain patients in clinical remission to help reduce the long-term risks and enhance cost-effectiveness. This ongoing debate highlights the need for efficient criteria to facilitate individualized decisions on anti-TNF discontinuation. We aimed to conduct an updated systematic review and meta-analysis pooling all RCTs published to date on this subject in order to provide a more robust assessment of the risk of relapse, the likelihood of sustained clinical remission, and the incidence of adverse events among patients with IBD in sustained clinical remission on TNF-α antagonists. By synthesizing all available evidence, our study seeks to enhance statistical power and provide more reliable estimates to guide clinical decision-making. 2. METHODS This meta-analysis was done in line with guidelines provided in the Cochrane Handbook for Systematic Reviews of Interventions and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement [ 11 , 12 ]. The protocol was prospectively registered with PROSPERO (CRD420251142276). 2.1 Data sources and searches We conducted extensive electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (via Ovid), Embase (via Ovid), and ClinicalTrials.gov, with no language restrictions, from inception to July 2025. We screened the reference lists of included studies and similar systematic reviews to further identify relevant studies. The detailed search strategies for each database are provided in Table S1 . 2.2 Eligibility criteria We included studies that fulfilled the following PICOS criteria: (1) population: patients diagnosed with IBD in remission; (2) intervention: withdrawal of TNF antagonist; (3) comparator: continuation of TNF antagonist; (4) outcomes: any outcome of interest as defined below; and (5) study type: RCTs. We excluded observational studies, non-randomized interventional studies, opinion pieces, and case reports. 2.3 Study selection and data extraction All relevant literatures from our searches were uploaded to Rayyan, where two reviewers independently screened the titles and abstracts, followed by full-text screening. Any disagreements between the reviewers were resolved by an arbitrator. Data on study characteristics (including authors and study design), patient population (including age, gender, disease duration, follow-up, and treatment duration), interventions, comparator details, and outcomes were extracted into a structured Excel spreadsheet. In case of missing or unclear data, we attempted to get relevant additional information from the study authors. 2.4 Outcomes The primary outcomes assessed were the risk of relapse and sustained clinical remission. The secondary outcomes included time to relapse, infection, gastrointestinal (GI) adverse events, and serious adverse events. 2.5 Risk of bias assessment We used the revised Cochrane Risk of Bias Tool for RCTs (RoB 2.0) to evaluate the risk of bias in the studies included in our analysis [ 13 ]. RoB 2.0 assesses bias in five domains: (1) bias resulting from the randomization process; (2) bias due to deviations from intended interventions; (3) bias due to missing outcome data; (4) bias in the measurement of the outcome; and (5) bias in the selection of the reported result. Two investigators evaluated the risk of bias for each included study as either high, low or some concerns of bias. Any differences in opinion regarding the risk of bias assessment were settled by a senior investigator. 2.6 Data analysis Meta-analyses were conducted using Review Manager (RevMan) 5.4, employing a random-effects model with the DerSimonian-Laird variance estimator [ 14 ]. Risk ratios (RRs) or hazard ratios (HRs) were pooled as effect measures for outcomes along with corresponding 95% confidence intervals (95% CIs). Heterogeneity was assessed using the I ² statistic. I² values of 75% indicated low, moderate, and high heterogeneity, respectively [ 15 ]. We conducted a subgroup analysis for our primary outcomes based on whether the trials included a placebo control. Publication bias could not be assessed as there were fewer than 10 studies in the review. 3.0 RESULTS 3.1 Study selection and characteristics A comprehensive search of databases and registers yielded 1407 records. After removing 458 duplicates, titles and abstracts were screened, leading to the exclusion of 911 irrelevant studies. Full-text articles of 38 reports were then assessed for eligibility, of which 4 RCTs fulfilled the predefined inclusion criteria and were incorporated into the meta-analysis [ 7 , 9 , 10 , 16 ]. The study selection process is illustrated in the PRISMA flowchart ( Figure S1 ). The four included RCTs were conducted across diverse regions, including the Nordic countries, Spain, Japan, and multiple international centers. Collectively, the studies enrolled 485 patients with Crohn’s disease (CD) and/or ulcerative colitis (UC), with sample sizes ranging from 92 to 138 participants in individual RCTs. The intervention arms primarily investigated infliximab withdrawal, although the EXIT trial also included patients treated with adalimumab. The mean or median follow-up duration ranged from 11 months to 2 years. Across studies, patient demographics were broadly comparable. Median or mean ages ranged from the early 30s to the mid-40s across the continuation and withdrawal groups, with approximately one-third to one-half of participants being female. Disease duration was typically 4–6 years. The duration of prior anti-TNF therapy before randomization spanned from 2 to 4 years, with HAYABUSA reporting a mean of over 3 years. The detailed baseline characteristics are reported in Table 1 . Table 1 Characteristics of included studies. Study Name Buhl 2022 (STOP IT) Gisbert 2025 (EXIT) Kobayashi 2021 (HAYABUSA) Louis 2022 (SPARE) Location Nordic countries Spain Japan Global Disease CD UC or CD UC CD Follow-up 11 months 1 year 12 months 2 years Intervention infliximab infliximab or adalimumab infliximab infliximab Comparator placebo placebo discontinuation without placebo discontinuation without placebo Definition of remission Clinical: CDAI < 150 Biochemical: normal CRP, WBC, Hgb, albumin Endoscopic: absence of signs of inflammatory activity on ileocolonoscopy + SES-CD 2 (SB inflammation evaluated by MRI and/or capsule endoscopy Clinical remission was defined for patients with CD as a Crohn’s Disease Activity Index (CDAI) score < 150 points, while for patients with UC remission was defined as a Partial Mayo Score (PMS) ≤ 2, with all subscores from the partial score being ≤ 1, and a rectal bleeding subscore of 0 CAI 4; corticosteroid-free remission Mayo Endoscopic Score of 0 or 1 No addition of UC-related meds after enrollment Steroid-free clinical remission based on retrospective assessment of pt medical files, CDAI 70 pts above baseline over 2 consecutive weeks OR definitive clinical relapse requiring immediate intervention Clinical relapse was defined as a CDAI > 150 points or a PMS > 2 (as applicable) in two consecutive visits separated by at least 1 week. when additional UC treatment for symptomatic worsening was required, or MES 2 during follow-up CDAI of 250 at any visit or CDAI 150–250 w/ an increase of at least 70 pts over 2 consecutive visits 1 wk apart CRP > 5 mg/L or FC > 250 mg/g Primary endpoint time to relapse sustained clinical remission at 12 months sustained clinical remission at 12 months sustained clinical remission at 12 months No. of patients Continuation 59 70 46 67 Withdrawal 56 70 46 71 Age of patients Continuation 36 (26–50) 41 ± 13 46.1 ± 13.4 36 (27–45.5) Withdrawal 32 (25–50) 41 ± 12 41.1 ± 15.6 32 (25–42.5) % of females Continuation 44.1 43 47.2 45 Withdrawal 50 31 32.6 39 Duration of disease Continuation 6 (3–12) years NR 4.3 (2.2–12.1) years NR Withdrawal 5 (3–15) years NR 5.4 (1.7–8.8) years NR Duration of therapy prior to intervention Continuation 24 (16–51) months 2.9 (1.7–4.8) years 166.1 (93.9–228.7) weeks 2.3 (1.5–3.6) years Withdrawal 21 (16–34) months 2.6 (1.2–5.7) years 164.6 (76.1–264) weeks 2.5 (1.4–4.5) years CDAI: Crohn’s Disease Activity Index, UC: Ulcerative Colitis, CD: Crohn’s Disease, CRP: C-reactive protein, WBC: White blood cell count, Hgb: Hemoglobin, SES-CD: Simple Endoscopic Score for Crohn’s Disease, MRI: Magnetic Resonance Imaging, PMS: Partial Mayo Score, CAI: Clinical Activity Index, MES: Mayo Endoscopic Score, UC meds: Ulcerative colitis-related medications, pt: Patient, FC: Fecal calprotectin, NR: Not reported 3.2 Risk of bias in included studies Two studies [ 7 , 10 ] were found to be of low risk of bias. The other two studies were found to have some concerns of bias due to deviations from the intended interventions and measurement of the outcome [ 9 , 16 ]. The detailed risk of bias is reported in Fig. 1 . 3.3 Results of the meta-analysis 3.3.1 Primary outcomes Relapse Our meta-analysis of the 4 RCTs showed a statistically significant increased risk of relapse in the TNF antagonist withdrawal group (RR: 3.00, 95% CI: 1.47–6.11, p = 0.002), with a moderate level of heterogeneity reported from the studies ( I 2 = 50%, Fig. 2 A). The results were consistent in both trials with and without a placebo control ( P for interaction = 0.52; Figure S2 ). Sustained clinical remission There was no significant difference in sustained clinical remission between the two groups (RR: 0.83, 95% CI: 0.55–1.27, p = 0.39). A high level of heterogeneity was observed ( I 2 = 83%, Fig. 2 B). The results were consistent in both trials with and without a placebo control ( P for interaction = 0.32; Figure S3 ). 3.3.2 Secondary outcomes On pooled analysis, the time to relapse was significantly shorter in the withdrawal group (HR: 5.34, 95% CI: 2.05–13.92, p = 0.0006, I 2 = 65%, Fig. 2 C) and the risk of infection was lower (RR: 0.47, 95% CI: 0.25–0.90, p = 0.02, I 2 = 0%, Fig. 3 A) compared to the continuation group. The risks of GI adverse events (RR:0.82, 95% CI 0.29–2.32, p = 0.71, I 2 = 27%, Fig. 3 B) and serious adverse events (RR:1.02, 95% CI 0.51–2.03, p = 0.95, I 2 = 0%, Fig. 3 C) were comparable in both groups. 4. DISCUSSION Our meta-analysis of 485 patients demonstrated that discontinuation of TNF antagonists increases the risk of clinical relapse in IBD patients. Relapse was three times more likely to occur in patients who quit medication than in those who continued. Furthermore, the withdrawal group experienced relapse earlier, suggesting both a shorter time to disease return and a higher chance of relapse. Although the risk of sustained clinical remission did not differ significantly between the two groups, TNF withdrawal was associated with a reduced risk of infections. Gastrointestinal adverse and serious adverse events were also not significantly different across the two groups, suggesting that TNF withdrawal makes no meaningful difference to serious adverse events beyond relapse. Our meta-analysis reveals several key findings that have important clinical implications. First, TNF antagonist withdrawal was associated with a statistically significant increase in relapse risk compared to patients continuing therapy. This finding aligns with previous observations from the broader meta-analysis by Katibian et al., which reported a 2.4-fold increased risk of relapse with TNF withdrawal, though our analysis provides a more focused assessment with updated data specifically targeting this intervention strategy [ 8 ].The magnitude of relapse risk observed in our study is clinically significant and warrants careful consideration when contemplating treatment de-escalation [ 17 , 18 ]. This information is crucial for shared decision-making between clinicians and patients. Second, our analysis demonstrated that TNF antagonist withdrawal significantly shortened the time to relapse, indicating not only an increased risk of relapse but also an acceleration in the timing of disease recurrence. This finding has practical implications for monitoring strategies, as patients who discontinue TNF therapy may require more intensive surveillance during the initial months following withdrawal [ 19 ]. Interestingly, our analysis revealed a reduced risk of infections in the TNF withdrawal group, which was expected given the immunosuppressive effects of TNF antagonists [ 20 ]. This finding supports the theoretical benefits of treatment de-escalation in terms of reducing infection-related morbidity [ 20 , 21 ]. However, the risks of gastrointestinal adverse events and serious adverse events were comparable between groups, suggesting that continuation of therapy maintains an acceptable safety profile. The reduced infection risk must be weighed against the increased relapse risk when counseling patients about treatment options. For patients at high risk for infections or those who have experienced recurrent infections on combination therapy, the trade-off between infection prevention and disease control becomes an important consideration in individualized treatment plans [ 22 – 24 ]. The decision to discontinue TNF antagonists should not be made uniformly for all patients in remission. Several factors may influence the risk-benefit ratio of treatment withdrawal. While our analysis could not identify consistent predictive factors due to limited reporting across studies, the literature suggests that patients with uncomplicated disease behavior, limited disease extent, absence of prior surgical interventions, and good biochemical markers may be better candidates for withdrawal attempts [ 23 , 25 ]. The heterogeneity observed in sustained clinical remission outcomes (I² = 83%) suggests that patient selection criteria and outcome definitions varied across studies, highlighting the need for standardized approaches to assess suitability for treatment de-escalation. Future research should focus on developing validated prediction tools to identify patients most likely to maintain remission following TNF withdrawal. 4.1 Clinical Practice Implications Based on our findings, TNF antagonist withdrawal should be approached with caution and reserved for carefully selected patients. The decision should involve a thorough discussion of the increased relapse risk and implementation of appropriate monitoring strategies. Patients should be counseled about the 3-fold increase in relapse risk and the accelerated time to relapse, while also being informed about the potential benefits, including reduced infection risk and cost savings. For patients who choose to proceed with TNF withdrawal, close monitoring, including regular clinical assessments and biochemical markers, is essential. The development of standardized protocols for monitoring and re-treatment following relapse would help optimize outcomes for patients attempting treatment de-escalation. 4.2 Future Research Directions Several areas warrant further investigation to optimize treatment de-escalation strategies in IBD. First, longer-term studies are needed to assess the durability of treatment effects and identify late complications of TNF withdrawal. Second, research focused on developing and validating predictive models for successful withdrawal would enable more precise patient selection. Third, studies examining the optimal timing and approach for re-initiation of TNF antagonists following relapse would inform clinical practice guidelines. Fourth, more RCTs are needed to investigate CD and UC separately, providing data for these distinct phenotypes. Additionally, comparative effectiveness research examining different withdrawal strategies, including dose reduction before complete discontinuation, may yield alternative approaches that balance efficacy and safety. The role of novel biomarkers and precision medicine approaches in guiding withdrawal decisions represents another promising avenue for future research. 4.3 Study Limitations Several limitations should be acknowledged when interpreting our findings. First, the included studies exhibited some heterogeneity in patient populations, with variations in disease duration, previous treatment history, and criteria for defining remission. This heterogeneity may limit the generalizability of our findings to specific patient subgroups. Second, the follow-up duration in the included studies was relatively short (11 months to 2 years), which may not capture long-term outcomes of TNF withdrawal. Longer-term studies are needed to assess the durability of treatment effects and the long-term safety implications of withdrawal strategies. Third, the definition of relapse varied across studies, potentially introducing heterogeneity in outcome assessment. Standardized definitions of disease relapse and remission would enhance the comparability of future studies in this area. Fourth, our analysis was limited to four studies, which restricted our ability to perform comprehensive subgroup analyses and assess publication bias. Fifth, we did not include conference abstracts to ensure data quality and methodological consistency, as they often lack peer review and the detailed reporting needed for quantitative synthesis and risk-of-bias assessment. Additionally, we restricted our analysis to RCTs to preserve internal validity and avoid confounding bias and heterogeneity associated with observational studies. Sixth, most studies focused on infliximab, limiting the generalizability to other TNF antagonists. Seventh, some included trials used placebo controls while others were open-label; however, subgroup analysis by control type did not show a significant interaction, suggesting that the control design did not influence the pooled estimates. Eighth, the EXIT trial included both UC and CD patients but did not report outcomes separately; consequently, we were unable to derive disease-specific pooled estimates for all studies. Future randomized trials should report outcomes by phenotype to enable stratified analyses. Finally, we focused our research question on complete treatment discontinuation rather than dose de-escalation strategies, which represent distinct clinical approaches with different therapeutic aims and risk considerations; this was done to keep our studies homogeneous and increase the reliability of the analysis. 5. CONCLUSION Our meta-analysis of 4 RCTs with 485 patients provides evidence that TNF antagonist withdrawal in patients with IBD in sustained clinical remission is associated with a significantly increased risk of disease relapse and shortened time to relapse. While withdrawal may reduce infection risk, the substantial increase in relapse rate necessitates careful patient selection and comprehensive counseling. These findings support the continued use of TNF antagonists in most patients who achieve sustained remission on combination therapy, with withdrawal considered only for selected patients after a thorough risk-benefit assessment and appropriate monitoring. The development of validated predictive tools and standardized withdrawal protocols will be essential to optimize outcomes for patients considering treatment de-escalation. Declarations Financial support No financial support was received for this study. Conflicts of interest The authors report no relationships that could be construed as a conflict of interest. Author Contribution Study concept and design were led by AAO, IQ, NA, MAA, HAC, and MAZ. Literature search and data collection were performed by NA, IQ, and MAA. Statistical analysis and interpretation of data were carried out by NA, MAA, MAZ, TRC, AK, and DG. Drafting of the manuscript was undertaken by AAO with substantial input from IQ, NA, MAA, MAZ, TRC, DG, AK, and AA. Revision of the manuscript for important intellectual content was performed by all authors. Study supervision was provided by HAC, AMAA, ER, AB, FA, and PKJ. All authors read and approved the final version of the manuscript. Acknowledgments Not applicable. Data Availability The data that support the findings of this study are available from the corresponding author upon reasonable request. References de Mattos BRR, Garcia MPG, Nogueira JB et al (2015) Inflammatory Bowel Disease: An Overview of Immune Mechanisms and Biological Treatments. Mediators Inflamm 2015:493012. https://doi.org/10.1155/2015/493012 Billmeier U, Dieterich W, Neurath MF, Atreya R (2016) Molecular mechanism of action of anti-tumor necrosis factor antibodies in inflammatory bowel diseases. World J Gastroenterol 22:9300–9313. https://doi.org/10.3748/wjg.v22.i42.9300 Torres J, Cravo M, Colombel J-F (2016) Anti-TNF Withdrawal in Inflammatory Bowel Disease. GE Port J Gastroenterol 23:153–161. https://doi.org/10.1016/j.jpge.2015.11.004 Feuerstein JD, Ho EY, Shmidt E et al (2021) AGA Clinical Practice Guidelines on the Medical Management of Moderate to Severe Luminal and Perianal Fistulizing Crohn’s Disease. Gastroenterology 160:2496–2508. https://doi.org/10.1053/j.gastro.2021.04.022 Singh S, Loftus EV, Limketkai BN et al (2024) AGA Living Clinical Practice Guideline on Pharmacological Management of Moderate-to-Severe Ulcerative Colitis. Gastroenterology 167:1307–1343. https://doi.org/10.1053/j.gastro.2024.10.001 Lamb CA, Kennedy NA, Raine T et al (2019) British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut 68:s1–s106. https://doi.org/10.1136/gutjnl-2019-318484 Buhl S, Steenholdt C, Brynskov J et al (2022) Discontinuation of Infliximab Therapy in Patients with Crohn’s Disease. NEJM Evid 1:EVIDoa2200061. https://doi.org/10.1056/EVIDoa2200061 Katibian DJ, Solitano V, Polk DB et al (2024) Withdrawal of Immunomodulators or TNF Antagonists in Patients With Inflammatory Bowel Diseases in Remission on Combination Therapy: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 22:22–33e6. https://doi.org/10.1016/j.cgh.2023.08.039 Louis E, Resche-Rigon M, Laharie D et al (2023) Withdrawal of infliximab or concomitant immunosuppressant therapy in patients with Crohn’s disease on combination therapy (SPARE): a multicentre, open-label, randomised controlled trial. Lancet Gastroenterol Hepatol 8:215–227. https://doi.org/10.1016/S2468-1253(22)00385-5 Gisbert JP, Donday MG, Riestra S et al (2025) Withdrawal of antitumour necrosis factor in inflammatory bowel disease patients in remission: a randomised placebo-controlled clinical trial of GETECCU. Gut 74:387–396. https://doi.org/10.1136/gutjnl-2024-333385 Higgins JP, Thomas J, Chandler J et al (2019) Cochrane handbook for systematic reviews of interventions. https://doi.org/10.1002/9781119536604 Page MJ, McKenzie JE, Bossuyt PM et al (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372:n71. https://doi.org/10.1136/bmj.n71 Sterne JA, Savović J, Page MJ et al (2019) RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 366:l4898 DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188. https://doi.org/10.1016/0197-2456(86)90046-2 Higgins JPT, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560. https://doi.org/10.1136/bmj.327.7414.557 Kobayashi T, Motoya S, Nakamura S et al (2021) Discontinuation of infliximab in patients with ulcerative colitis in remission (HAYABUSA): a multicentre, open-label, randomised controlled trial. Lancet Gastroenterol Hepatol 6:429–437. https://doi.org/10.1016/S2468-1253(21)00062-5 Torres J, Bonovas S, Doherty G et al (2020) ECCO Guidelines on Therapeutics in Crohn’s Disease: Medical Treatment. J Crohns Colitis 14:4–22. https://doi.org/10.1093/ecco-jcc/jjz180 Targownik LE, Benchimol EI, Bernstein CN et al (2020) Combined Biologic and Immunomodulatory Therapy is Superior to Monotherapy for Decreasing the Risk of Inflammatory Bowel Disease-Related Complications. J Crohns Colitis 14:1354–1363. https://doi.org/10.1093/ecco-jcc/jjaa050 Colombel JF, Sandborn WJ, Reinisch W et al (2010) Infliximab, Azathioprine, or Combination Therapy for Crohn’s Disease. N Engl J Med 362:1383–1395. https://doi.org/10.1056/NEJMoa0904492 Kirchgesner J, Lemaitre M, Carrat F et al (2018) Risk of Serious and Opportunistic Infections Associated With Treatment of Inflammatory Bowel Diseases. Gastroenterology 155:337–346e10. https://doi.org/10.1053/j.gastro.2018.04.012 Singh S, Facciorusso A, Dulai PS et al (2020) Comparative Risk of Serious Infections With Biologic and/or Immunosuppressive Therapy in Patients With Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc 18:69–81e3. https://doi.org/10.1016/j.cgh.2019.02.044 Yang S, Yang S, Kwon Jo Y et al (2021) Efficacy and tolerability of infliximab retreatment in patients with inflammatory bowel disease: a systematic review and meta-analysis. Ther Adv Chronic Dis 12:20406223211041927. https://doi.org/10.1177/20406223211041927 Torres J, Boyapati RK, Kennedy NA et al (2015) Systematic Review of Effects of Withdrawal of Immunomodulators or Biologic Agents From Patients With Inflammatory Bowel Disease. Gastroenterology 149:1716–1730. https://doi.org/10.1053/j.gastro.2015.08.055 Kennedy NA, Heap GA, Green HD et al (2019) Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn’s disease: a prospective, multicentre, cohort study. Lancet Gastroenterol Hepatol 4:341–353. https://doi.org/10.1016/S2468-1253(19)30012-3 Pauwels RWM, van der Woude CJ, Nieboer D et al (2022) Prediction of Relapse After Anti-Tumor Necrosis Factor Cessation in Crohn’s Disease: Individual Participant Data Meta-analysis of 1317 Patients From 14 Studies. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc 20:1671–1686e16. https://doi.org/10.1016/j.cgh.2021.03.037 van der Valk ME, Mangen M-JJ, Leenders M et al (2014) Healthcare costs of inflammatory bowel disease have shifted from hospitalisation and surgery towards anti-TNFα therapy: results from the COIN study. Gut 63:72–79. https://doi.org/10.1136/gutjnl-2012-303376 Chapman TP, Gomes CF, Louis E et al (2020) De-escalation of immunomodulator and biological therapy in inflammatory bowel disease. Lancet Gastroenterol Hepatol 5:63–79. https://doi.org/10.1016/S2468-1253(19)30186-4 Doherty G, Katsanos KH, Burisch J et al (2018) European Crohn’s and Colitis Organisation Topical Review on Treatment Withdrawal [’Exit Strategies’] in Inflammatory Bowel Disease. J Crohns Colitis 12:17–31. https://doi.org/10.1093/ecco-jcc/jjx101 Additional Declarations No competing interests reported. Supplementary Files SupplementaryAppendix.docx Cite Share Download PDF Status: Published Journal Publication published 02 Dec, 2025 Read the published version in International Journal of Colorectal Disease → Version 1 posted Editorial decision: Accepted 24 Nov, 2025 Reviews received at journal 20 Nov, 2025 Reviewers agreed at journal 19 Nov, 2025 Reviewers invited by journal 19 Nov, 2025 Submission checks completed at journal 04 Nov, 2025 First submitted to journal 03 Nov, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7842211","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":542008695,"identity":"1e323003-976d-4ad0-801b-6f3c81b4c58e","order_by":0,"name":"Ahmed Adekunle Owolabi","email":"","orcid":"","institution":"Stockport NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Ahmed","middleName":"Adekunle","lastName":"Owolabi","suffix":""},{"id":542008696,"identity":"87884a8f-80ca-4fc3-9440-964c91fe5164","order_by":1,"name":"Iqra Qazi","email":"","orcid":"","institution":"Baptist Hospitals of Southeast 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Center","correspondingAuthor":false,"prefix":"","firstName":"Muhammad","middleName":"Abu","lastName":"Zar","suffix":""},{"id":542008700,"identity":"84e3a283-ac3c-4a53-9528-45c903754c66","order_by":5,"name":"Taimour Rashid Choudhry","email":"","orcid":"","institution":"Kettering General Hospital NHS Trust","correspondingAuthor":false,"prefix":"","firstName":"Taimour","middleName":"Rashid","lastName":"Choudhry","suffix":""},{"id":542008701,"identity":"c26b53d6-839c-4e59-8fa1-78c3301e21cb","order_by":6,"name":"Dhanushan Gnanendran","email":"","orcid":"","institution":"University Hospitals Plymouth NHS Trust","correspondingAuthor":false,"prefix":"","firstName":"Dhanushan","middleName":"","lastName":"Gnanendran","suffix":""},{"id":542008702,"identity":"1ab9993a-1fe5-4328-ade1-29bad9c54f67","order_by":7,"name":"Aqsa Khan","email":"","orcid":"","institution":"Parkview 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17:16:15","extension":"html","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":104996,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7842211/v1/1d9f5ce4db642152e777dce6.html"},{"id":95798766,"identity":"1924baa7-de13-48f6-b3e0-75a9edb5f8b5","added_by":"auto","created_at":"2025-11-13 08:17:45","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":276684,"visible":true,"origin":"","legend":"\u003cp\u003eRisk of bias assessment for included RCTs\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7842211/v1/231eba97395b31fdc7ec1408.jpg"},{"id":95670010,"identity":"13fc2655-d5af-4dc8-a054-a8a52a6f2ff2","added_by":"auto","created_at":"2025-11-11 17:16:15","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":214010,"visible":true,"origin":"","legend":"\u003cp\u003eForest plots for (A) relapse (B) sustained clinical remission, and (C) time to relapse\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7842211/v1/dfb886b2923d9e7e120b60e5.jpg"},{"id":95670015,"identity":"72ef569d-0039-48cd-9f65-f9d1730fd742","added_by":"auto","created_at":"2025-11-11 17:16:15","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":215490,"visible":true,"origin":"","legend":"\u003cp\u003eForest plots for (A) risk of infection (B) GI adverse events, and (C) serious adverse events\u003c/p\u003e\n\u003cp\u003eGI: gastrointestinal\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7842211/v1/00ecd5203ac57295d99d9577.jpg"},{"id":97723951,"identity":"aaaf62c9-d8c1-45eb-9a26-a02db1b7596c","added_by":"auto","created_at":"2025-12-08 16:10:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1626899,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7842211/v1/05aa271b-a40b-4361-9347-af709ba1ddb8.pdf"},{"id":95799308,"identity":"e7d37c77-d560-46de-adf8-d5cf438a01fc","added_by":"auto","created_at":"2025-11-13 08:19:27","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":74503,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryAppendix.docx","url":"https://assets-eu.researchsquare.com/files/rs-7842211/v1/d389e593824afb43252194d4.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Withdrawal of TNF Antagonists in Patients with Inflammatory Bowel Disease in Remission: A Systematic Review and Meta-analysis of Randomized Controlled Trials","fulltext":[{"header":"1. INTRODUCTION","content":"\u003cp\u003eThe early advent of tumor necrosis factor (TNF) antagonists has significantly impacted the management of inflammatory bowel disease (IBD). These agents effectively control the progressive nature of IBD, enabling many patients to achieve remission while reducing the need for invasive interventions and hospitalizations [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Combination therapy with anti-TNF agents and immunomodulators (IMMs) has been proven to be effective in inducing and maintaining clinical and endoscopic remission, especially in patients with Crohn\u0026rsquo;s disease (CD) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Unfortunately, prolonged combination therapy can be concerning regarding long-term safety risks, infections, and considerable costs [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eConsequently, the discontinuation of IMM or the anti-TNF agents in IBD patients who achieved a sustained clinical remission has become an essential question in clinical practice. While IMM withdrawal has not consistently shown an increase in relapse rates, several randomized controlled trials (RCTs) suggest that anti-TNF withdrawal could be associated with significantly higher relapse rates [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Studies show a statistically significant relapse rate of 31.5% at 1\u0026ndash;2 years following anti-TNF withdrawal, compared with 12% among those who continued combination therapy [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, some studies have shown that withdrawal of anti-TNF agents does not significantly impact the relapse rates in patients with IBD [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Despite the inconsistent heterogeneous data, discontinuation of anti-TNF therapy remains a potential strategy for certain patients in clinical remission to help reduce the long-term risks and enhance cost-effectiveness. This ongoing debate highlights the need for efficient criteria to facilitate individualized decisions on anti-TNF discontinuation.\u003c/p\u003e\u003cp\u003eWe aimed to conduct an updated systematic review and meta-analysis pooling all RCTs published to date on this subject in order to provide a more robust assessment of the risk of relapse, the likelihood of sustained clinical remission, and the incidence of adverse events among patients with IBD in sustained clinical remission on TNF-α antagonists. By synthesizing all available evidence, our study seeks to enhance statistical power and provide more reliable estimates to guide clinical decision-making.\u003c/p\u003e"},{"header":"2. METHODS","content":"\u003cp\u003eThis meta-analysis was done in line with guidelines provided in the \u003cem\u003eCochrane Handbook for Systematic Reviews of Interventions\u003c/em\u003e and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The protocol was prospectively registered with PROSPERO (CRD420251142276).\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Data sources and searches\u003c/h2\u003e\u003cp\u003eWe conducted extensive electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (via Ovid), Embase (via Ovid), and ClinicalTrials.gov, with no language restrictions, from inception to July 2025. We screened the reference lists of included studies and similar systematic reviews to further identify relevant studies. The detailed search strategies for each database are provided in \u003cb\u003eTable \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/b\u003e.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Eligibility criteria\u003c/h2\u003e\u003cp\u003eWe included studies that fulfilled the following PICOS criteria: (1) population: patients diagnosed with IBD in remission; (2) intervention: withdrawal of TNF antagonist; (3) comparator: continuation of TNF antagonist; (4) outcomes: any outcome of interest as defined below; and (5) study type: RCTs. We excluded observational studies, non-randomized interventional studies, opinion pieces, and case reports.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Study selection and data extraction\u003c/h2\u003e\u003cp\u003eAll relevant literatures from our searches were uploaded to Rayyan, where two reviewers independently screened the titles and abstracts, followed by full-text screening. Any disagreements between the reviewers were resolved by an arbitrator.\u003c/p\u003e\u003cp\u003eData on study characteristics (including authors and study design), patient population (including age, gender, disease duration, follow-up, and treatment duration), interventions, comparator details, and outcomes were extracted into a structured Excel spreadsheet. In case of missing or unclear data, we attempted to get relevant additional information from the study authors.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4 Outcomes\u003c/h2\u003e\u003cp\u003eThe primary outcomes assessed were the risk of relapse and sustained clinical remission. The secondary outcomes included time to relapse, infection, gastrointestinal (GI) adverse events, and serious adverse events.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e2.5 Risk of bias assessment\u003c/h2\u003e\u003cp\u003eWe used the revised Cochrane Risk of Bias Tool for RCTs (RoB 2.0) to evaluate the risk of bias in the studies included in our analysis [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. RoB 2.0 assesses bias in five domains: (1) bias resulting from the randomization process; (2) bias due to deviations from intended interventions; (3) bias due to missing outcome data; (4) bias in the measurement of the outcome; and (5) bias in the selection of the reported result. Two investigators evaluated the risk of bias for each included study as either high, low or some concerns of bias. Any differences in opinion regarding the risk of bias assessment were settled by a senior investigator.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e2.6 Data analysis\u003c/h2\u003e\u003cp\u003eMeta-analyses were conducted using Review Manager (RevMan) 5.4, employing a random-effects model with the DerSimonian-Laird variance estimator [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Risk ratios (RRs) or hazard ratios (HRs) were pooled as effect measures for outcomes along with corresponding 95% confidence intervals (95% CIs). Heterogeneity was assessed using the \u003cem\u003eI\u003c/em\u003e\u0026sup2; statistic. I\u0026sup2; values of \u0026lt;\u0026thinsp;50%, 50%\u0026minus;75%, and \u0026gt;\u0026thinsp;75% indicated low, moderate, and high heterogeneity, respectively [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. We conducted a subgroup analysis for our primary outcomes based on whether the trials included a placebo control.\u003c/p\u003e\u003cp\u003ePublication bias could not be assessed as there were fewer than 10 studies in the review.\u003c/p\u003e\u003c/div\u003e"},{"header":"3.0 RESULTS","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e3.1 Study selection and characteristics\u003c/h2\u003e\u003cp\u003eA comprehensive search of databases and registers yielded 1407 records. After removing 458 duplicates, titles and abstracts were screened, leading to the exclusion of 911 irrelevant studies. Full-text articles of 38 reports were then assessed for eligibility, of which 4 RCTs fulfilled the predefined inclusion criteria and were incorporated into the meta-analysis [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The study selection process is illustrated in the PRISMA flowchart (\u003cb\u003eFigure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/b\u003e).\u003c/p\u003e\u003cp\u003eThe four included RCTs were conducted across diverse regions, including the Nordic countries, Spain, Japan, and multiple international centers. Collectively, the studies enrolled 485 patients with Crohn\u0026rsquo;s disease (CD) and/or ulcerative colitis (UC), with sample sizes ranging from 92 to 138 participants in individual RCTs. The intervention arms primarily investigated infliximab withdrawal, although the EXIT trial also included patients treated with adalimumab. The mean or median follow-up duration ranged from 11 months to 2 years. Across studies, patient demographics were broadly comparable. Median or mean ages ranged from the early 30s to the mid-40s across the continuation and withdrawal groups, with approximately one-third to one-half of participants being female. Disease duration was typically 4\u0026ndash;6 years. The duration of prior anti-TNF therapy before randomization spanned from 2 to 4 years, with HAYABUSA reporting a mean of over 3 years. The detailed baseline characteristics are reported in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCharacteristics of included studies.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStudy Name\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBuhl 2022 (STOP IT)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eGisbert 2025 (EXIT)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eKobayashi 2021 (HAYABUSA)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eLouis 2022 (SPARE)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLocation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNordic countries\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSpain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eJapan\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eGlobal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDisease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eUC or CD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCD\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFollow-up\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 year\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2 years\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIntervention\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003einfliximab\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003einfliximab or adalimumab\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003einfliximab\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003einfliximab\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eComparator\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eplacebo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eplacebo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ediscontinuation without placebo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ediscontinuation without placebo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDefinition of remission\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eClinical: CDAI\u0026thinsp;\u0026lt;\u0026thinsp;150\u003c/p\u003e\u003cp\u003eBiochemical: normal CRP, WBC, Hgb, albumin\u003c/p\u003e\u003cp\u003eEndoscopic: absence of signs of inflammatory activity on ileocolonoscopy\u0026thinsp;+\u0026thinsp;SES-CD 2 (SB inflammation evaluated by MRI and/or capsule endoscopy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eClinical remission was defined for patients with CD as a Crohn\u0026rsquo;s Disease Activity Index (CDAI) score\u0026thinsp;\u0026lt;\u0026thinsp;150 points, while for patients with UC remission was defined as a Partial Mayo Score (PMS)\u0026thinsp;\u0026le;\u0026thinsp;2, with all subscores from the partial score being \u0026le;\u0026thinsp;1, and a rectal bleeding subscore of 0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCAI 4; corticosteroid-free remission\u003c/p\u003e\u003cp\u003eMayo Endoscopic Score of 0 or 1\u003c/p\u003e\u003cp\u003eNo addition of UC-related meds after enrollment\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSteroid-free clinical remission based on retrospective assessment of pt medical files, CDAI\u0026thinsp;\u0026lt;\u0026thinsp;150 at baseline\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDefinition of relapse\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCDAI 150 w/ an increase in CDAI\u0026thinsp;\u0026gt;\u0026thinsp;70 pts above baseline over 2 consecutive weeks OR definitive clinical relapse requiring immediate intervention\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eClinical relapse was defined as a CDAI\u0026thinsp;\u0026gt;\u0026thinsp;150 points or a PMS\u0026thinsp;\u0026gt;\u0026thinsp;2 (as applicable) in two consecutive visits separated by at least 1 week.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ewhen additional UC treatment for symptomatic worsening was required, or MES 2 during follow-up\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCDAI of 250 at any visit or CDAI 150\u0026ndash;250 w/ an increase of at least 70 pts over 2 consecutive visits 1 wk apart\u003c/p\u003e\u003cp\u003eCRP\u0026thinsp;\u0026gt;\u0026thinsp;5 mg/L or FC\u0026thinsp;\u0026gt;\u0026thinsp;250 mg/g\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrimary endpoint\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003etime to relapse\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003esustained clinical remission at 12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003esustained clinical remission at 12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003esustained clinical remission at 12 months\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo. of patients\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eContinuation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e67\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWithdrawal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e71\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge of patients\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eContinuation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e36 (26\u0026ndash;50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e41\u0026thinsp;\u0026plusmn;\u0026thinsp;13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e46.1\u0026thinsp;\u0026plusmn;\u0026thinsp;13.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e36 (27\u0026ndash;45.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWithdrawal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e32 (25\u0026ndash;50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e41\u0026thinsp;\u0026plusmn;\u0026thinsp;12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e41.1\u0026thinsp;\u0026plusmn;\u0026thinsp;15.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e32 (25\u0026ndash;42.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e% of females\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eContinuation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e44.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e47.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e45\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWithdrawal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e32.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e39\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDuration of disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eContinuation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6 (3\u0026ndash;12) years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4.3 (2.2\u0026ndash;12.1) years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNR\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWithdrawal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (3\u0026ndash;15) years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5.4 (1.7\u0026ndash;8.8) years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNR\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDuration of therapy prior to intervention\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eContinuation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24 (16\u0026ndash;51) months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.9 (1.7\u0026ndash;4.8) years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e166.1 (93.9\u0026ndash;228.7) weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.3 (1.5\u0026ndash;3.6) years\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWithdrawal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e21 (16\u0026ndash;34) months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.6 (1.2\u0026ndash;5.7) years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e164.6 (76.1\u0026ndash;264) weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.5 (1.4\u0026ndash;4.5) years\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003eCDAI: Crohn\u0026rsquo;s Disease Activity Index, UC: Ulcerative Colitis, CD: Crohn\u0026rsquo;s Disease, CRP: C-reactive protein, WBC: White blood cell count, Hgb: Hemoglobin, SES-CD: Simple Endoscopic Score for Crohn\u0026rsquo;s Disease, MRI: Magnetic Resonance Imaging, PMS: Partial Mayo Score, CAI: Clinical Activity Index, MES: Mayo Endoscopic Score, UC meds: Ulcerative colitis-related medications, pt: Patient, FC: Fecal calprotectin, NR: Not reported\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e3.2 Risk of bias in included studies\u003c/h2\u003e\u003cp\u003eTwo studies [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] were found to be of low risk of bias. The other two studies were found to have some concerns of bias due to deviations from the intended interventions and measurement of the outcome [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The detailed risk of bias is reported in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e3.3 Results of the meta-analysis\u003c/h2\u003e\u003cdiv id=\"Sec13\" class=\"Section3\"\u003e\u003ch2\u003e3.3.1 Primary outcomes\u003c/h2\u003e\u003cp\u003e\u003cb\u003eRelapse\u003c/b\u003e\u003c/p\u003e\u003cp\u003eOur meta-analysis of the 4 RCTs showed a statistically significant increased risk of relapse in the TNF antagonist withdrawal group (RR: 3.00, 95% CI: 1.47\u0026ndash;6.11, p\u0026thinsp;=\u0026thinsp;0.002), with a moderate level of heterogeneity reported from the studies (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;50%, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). The results were consistent in both trials with and without a placebo control (\u003cem\u003eP\u003c/em\u003e for interaction\u0026thinsp;=\u0026thinsp;0.52; \u003cb\u003eFigure S2\u003c/b\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eSustained clinical remission\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThere was no significant difference in sustained clinical remission between the two groups (RR: 0.83, 95% CI: 0.55\u0026ndash;1.27, p\u0026thinsp;=\u0026thinsp;0.39). A high level of heterogeneity was observed (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;83%, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). The results were consistent in both trials with and without a placebo control (\u003cem\u003eP\u003c/em\u003e for interaction\u0026thinsp;=\u0026thinsp;0.32; \u003cb\u003eFigure S3\u003c/b\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section3\"\u003e\u003ch2\u003e3.3.2 Secondary outcomes\u003c/h2\u003e\u003cp\u003eOn pooled analysis, the time to relapse was significantly shorter in the withdrawal group (HR: 5.34, 95% CI: 2.05\u0026ndash;13.92, p\u0026thinsp;=\u0026thinsp;0.0006, \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;65%, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC) and the risk of infection was lower (RR: 0.47, 95% CI: 0.25\u0026ndash;0.90, p\u0026thinsp;=\u0026thinsp;0.02, \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA) compared to the continuation group.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe risks of GI adverse events (RR:0.82, 95% CI 0.29\u0026ndash;2.32, p\u0026thinsp;=\u0026thinsp;0.71, \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;27%, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB) and serious adverse events (RR:1.02, 95% CI 0.51\u0026ndash;2.03, p\u0026thinsp;=\u0026thinsp;0.95, \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC) were comparable in both groups.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"4. DISCUSSION","content":"\u003cp\u003eOur meta-analysis of 485 patients demonstrated that discontinuation of TNF antagonists increases the risk of clinical relapse in IBD patients. Relapse was three times more likely to occur in patients who quit medication than in those who continued. Furthermore, the withdrawal group experienced relapse earlier, suggesting both a shorter time to disease return and a higher chance of relapse. Although the risk of sustained clinical remission did not differ significantly between the two groups, TNF withdrawal was associated with a reduced risk of infections. Gastrointestinal adverse and serious adverse events were also not significantly different across the two groups, suggesting that TNF withdrawal makes no meaningful difference to serious adverse events beyond relapse.\u003c/p\u003e\u003cp\u003eOur meta-analysis reveals several key findings that have important clinical implications. First, TNF antagonist withdrawal was associated with a statistically significant increase in relapse risk compared to patients continuing therapy. This finding aligns with previous observations from the broader meta-analysis by Katibian et al., which reported a 2.4-fold increased risk of relapse with TNF withdrawal, though our analysis provides a more focused assessment with updated data specifically targeting this intervention strategy [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].The magnitude of relapse risk observed in our study is clinically significant and warrants careful consideration when contemplating treatment de-escalation [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. This information is crucial for shared decision-making between clinicians and patients.\u003c/p\u003e\u003cp\u003eSecond, our analysis demonstrated that TNF antagonist withdrawal significantly shortened the time to relapse, indicating not only an increased risk of relapse but also an acceleration in the timing of disease recurrence. This finding has practical implications for monitoring strategies, as patients who discontinue TNF therapy may require more intensive surveillance during the initial months following withdrawal [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Interestingly, our analysis revealed a reduced risk of infections in the TNF withdrawal group, which was expected given the immunosuppressive effects of TNF antagonists [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. This finding supports the theoretical benefits of treatment de-escalation in terms of reducing infection-related morbidity [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. However, the risks of gastrointestinal adverse events and serious adverse events were comparable between groups, suggesting that continuation of therapy maintains an acceptable safety profile. The reduced infection risk must be weighed against the increased relapse risk when counseling patients about treatment options. For patients at high risk for infections or those who have experienced recurrent infections on combination therapy, the trade-off between infection prevention and disease control becomes an important consideration in individualized treatment plans [\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe decision to discontinue TNF antagonists should not be made uniformly for all patients in remission. Several factors may influence the risk-benefit ratio of treatment withdrawal. While our analysis could not identify consistent predictive factors due to limited reporting across studies, the literature suggests that patients with uncomplicated disease behavior, limited disease extent, absence of prior surgical interventions, and good biochemical markers may be better candidates for withdrawal attempts [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. The heterogeneity observed in sustained clinical remission outcomes (I\u0026sup2; = 83%) suggests that patient selection criteria and outcome definitions varied across studies, highlighting the need for standardized approaches to assess suitability for treatment de-escalation. Future research should focus on developing validated prediction tools to identify patients most likely to maintain remission following TNF withdrawal.\u003c/p\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003e4.1 Clinical Practice Implications\u003c/h2\u003e\u003cp\u003eBased on our findings, TNF antagonist withdrawal should be approached with caution and reserved for carefully selected patients. The decision should involve a thorough discussion of the increased relapse risk and implementation of appropriate monitoring strategies. Patients should be counseled about the 3-fold increase in relapse risk and the accelerated time to relapse, while also being informed about the potential benefits, including reduced infection risk and cost savings.\u003c/p\u003e\u003cp\u003eFor patients who choose to proceed with TNF withdrawal, close monitoring, including regular clinical assessments and biochemical markers, is essential. The development of standardized protocols for monitoring and re-treatment following relapse would help optimize outcomes for patients attempting treatment de-escalation.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003e4.2 Future Research Directions\u003c/h2\u003e\u003cp\u003eSeveral areas warrant further investigation to optimize treatment de-escalation strategies in IBD. First, longer-term studies are needed to assess the durability of treatment effects and identify late complications of TNF withdrawal. Second, research focused on developing and validating predictive models for successful withdrawal would enable more precise patient selection. Third, studies examining the optimal timing and approach for re-initiation of TNF antagonists following relapse would inform clinical practice guidelines. Fourth, more RCTs are needed to investigate CD and UC separately, providing data for these distinct phenotypes.\u003c/p\u003e\u003cp\u003eAdditionally, comparative effectiveness research examining different withdrawal strategies, including dose reduction before complete discontinuation, may yield alternative approaches that balance efficacy and safety. The role of novel biomarkers and precision medicine approaches in guiding withdrawal decisions represents another promising avenue for future research.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003e4.3 Study Limitations\u003c/h2\u003e\u003cp\u003eSeveral limitations should be acknowledged when interpreting our findings. First, the included studies exhibited some heterogeneity in patient populations, with variations in disease duration, previous treatment history, and criteria for defining remission. This heterogeneity may limit the generalizability of our findings to specific patient subgroups. Second, the follow-up duration in the included studies was relatively short (11 months to 2 years), which may not capture long-term outcomes of TNF withdrawal. Longer-term studies are needed to assess the durability of treatment effects and the long-term safety implications of withdrawal strategies. Third, the definition of relapse varied across studies, potentially introducing heterogeneity in outcome assessment. Standardized definitions of disease relapse and remission would enhance the comparability of future studies in this area. Fourth, our analysis was limited to four studies, which restricted our ability to perform comprehensive subgroup analyses and assess publication bias. Fifth, we did not include conference abstracts to ensure data quality and methodological consistency, as they often lack peer review and the detailed reporting needed for quantitative synthesis and risk-of-bias assessment. Additionally, we restricted our analysis to RCTs to preserve internal validity and avoid confounding bias and heterogeneity associated with observational studies. Sixth, most studies focused on infliximab, limiting the generalizability to other TNF antagonists. Seventh, some included trials used placebo controls while others were open-label; however, subgroup analysis by control type did not show a significant interaction, suggesting that the control design did not influence the pooled estimates. Eighth, the EXIT trial included both UC and CD patients but did not report outcomes separately; consequently, we were unable to derive disease-specific pooled estimates for all studies. Future randomized trials should report outcomes by phenotype to enable stratified analyses. Finally, we focused our research question on complete treatment discontinuation rather than dose de-escalation strategies, which represent distinct clinical approaches with different therapeutic aims and risk considerations; this was done to keep our studies homogeneous and increase the reliability of the analysis.\u003c/p\u003e\u003c/div\u003e"},{"header":"5. CONCLUSION","content":"\u003cp\u003eOur meta-analysis of 4 RCTs with 485 patients provides evidence that TNF antagonist withdrawal in patients with IBD in sustained clinical remission is associated with a significantly increased risk of disease relapse and shortened time to relapse. While withdrawal may reduce infection risk, the substantial increase in relapse rate necessitates careful patient selection and comprehensive counseling. These findings support the continued use of TNF antagonists in most patients who achieve sustained remission on combination therapy, with withdrawal considered only for selected patients after a thorough risk-benefit assessment and appropriate monitoring. The development of validated predictive tools and standardized withdrawal protocols will be essential to optimize outcomes for patients considering treatment de-escalation.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cb\u003eFinancial support\u003c/b\u003e\u003c/p\u003e\u003cp\u003eNo financial support was received for this study.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003cp\u003eThe authors report no relationships that could be construed as a conflict of interest.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eStudy concept and design were led by AAO, IQ, NA, MAA, HAC, and MAZ. Literature search and data collection were performed by NA, IQ, and MAA. Statistical analysis and interpretation of data were carried out by NA, MAA, MAZ, TRC, AK, and DG. Drafting of the manuscript was undertaken by AAO with substantial input from IQ, NA, MAA, MAZ, TRC, DG, AK, and AA. Revision of the manuscript for important intellectual content was performed by all authors. Study supervision was provided by HAC, AMAA, ER, AB, FA, and PKJ. All authors read and approved the final version of the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgments\u003c/h2\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ede Mattos BRR, Garcia MPG, Nogueira JB et al (2015) Inflammatory Bowel Disease: An Overview of Immune Mechanisms and Biological Treatments. Mediators Inflamm 2015:493012. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1155/2015/493012\u003c/span\u003e\u003cspan address=\"10.1155/2015/493012\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBillmeier U, Dieterich W, Neurath MF, Atreya R (2016) Molecular mechanism of action of anti-tumor necrosis factor antibodies in inflammatory bowel diseases. World J Gastroenterol 22:9300\u0026ndash;9313. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3748/wjg.v22.i42.9300\u003c/span\u003e\u003cspan address=\"10.3748/wjg.v22.i42.9300\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTorres J, Cravo M, Colombel J-F (2016) Anti-TNF Withdrawal in Inflammatory Bowel Disease. GE Port J Gastroenterol 23:153\u0026ndash;161. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.jpge.2015.11.004\u003c/span\u003e\u003cspan address=\"10.1016/j.jpge.2015.11.004\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFeuerstein JD, Ho EY, Shmidt E et al (2021) AGA Clinical Practice Guidelines on the Medical Management of Moderate to Severe Luminal and Perianal Fistulizing Crohn\u0026rsquo;s Disease. Gastroenterology 160:2496\u0026ndash;2508. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1053/j.gastro.2021.04.022\u003c/span\u003e\u003cspan address=\"10.1053/j.gastro.2021.04.022\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSingh S, Loftus EV, Limketkai BN et al (2024) AGA Living Clinical Practice Guideline on Pharmacological Management of Moderate-to-Severe Ulcerative Colitis. Gastroenterology 167:1307\u0026ndash;1343. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1053/j.gastro.2024.10.001\u003c/span\u003e\u003cspan address=\"10.1053/j.gastro.2024.10.001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLamb CA, Kennedy NA, Raine T et al (2019) British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut 68:s1\u0026ndash;s106. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1136/gutjnl-2019-318484\u003c/span\u003e\u003cspan address=\"10.1136/gutjnl-2019-318484\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBuhl S, Steenholdt C, Brynskov J et al (2022) Discontinuation of Infliximab Therapy in Patients with Crohn\u0026rsquo;s Disease. NEJM Evid 1:EVIDoa2200061. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1056/EVIDoa2200061\u003c/span\u003e\u003cspan address=\"10.1056/EVIDoa2200061\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKatibian DJ, Solitano V, Polk DB et al (2024) Withdrawal of Immunomodulators or TNF Antagonists in Patients With Inflammatory Bowel Diseases in Remission on Combination Therapy: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 22:22\u0026ndash;33e6. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.cgh.2023.08.039\u003c/span\u003e\u003cspan address=\"10.1016/j.cgh.2023.08.039\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLouis E, Resche-Rigon M, Laharie D et al (2023) Withdrawal of infliximab or concomitant immunosuppressant therapy in patients with Crohn\u0026rsquo;s disease on combination therapy (SPARE): a multicentre, open-label, randomised controlled trial. Lancet Gastroenterol Hepatol 8:215\u0026ndash;227. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S2468-1253(22)00385-5\u003c/span\u003e\u003cspan address=\"10.1016/S2468-1253(22)00385-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGisbert JP, Donday MG, Riestra S et al (2025) Withdrawal of antitumour necrosis factor in inflammatory bowel disease patients in remission: a randomised placebo-controlled clinical trial of GETECCU. Gut 74:387\u0026ndash;396. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1136/gutjnl-2024-333385\u003c/span\u003e\u003cspan address=\"10.1136/gutjnl-2024-333385\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHiggins JP, Thomas J, Chandler J et al (2019) Cochrane handbook for systematic reviews of interventions. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/9781119536604\u003c/span\u003e\u003cspan address=\"10.1002/9781119536604\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePage MJ, McKenzie JE, Bossuyt PM et al (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372:n71. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1136/bmj.n71\u003c/span\u003e\u003cspan address=\"10.1136/bmj.n71\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSterne JA, Savović J, Page MJ et al (2019) RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 366:l4898\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177\u0026ndash;188. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/0197-2456(86)90046-2\u003c/span\u003e\u003cspan address=\"10.1016/0197-2456(86)90046-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHiggins JPT, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557\u0026ndash;560. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1136/bmj.327.7414.557\u003c/span\u003e\u003cspan address=\"10.1136/bmj.327.7414.557\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKobayashi T, Motoya S, Nakamura S et al (2021) Discontinuation of infliximab in patients with ulcerative colitis in remission (HAYABUSA): a multicentre, open-label, randomised controlled trial. Lancet Gastroenterol Hepatol 6:429\u0026ndash;437. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S2468-1253(21)00062-5\u003c/span\u003e\u003cspan address=\"10.1016/S2468-1253(21)00062-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTorres J, Bonovas S, Doherty G et al (2020) ECCO Guidelines on Therapeutics in Crohn\u0026rsquo;s Disease: Medical Treatment. J Crohns Colitis 14:4\u0026ndash;22. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/ecco-jcc/jjz180\u003c/span\u003e\u003cspan address=\"10.1093/ecco-jcc/jjz180\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTargownik LE, Benchimol EI, Bernstein CN et al (2020) Combined Biologic and Immunomodulatory Therapy is Superior to Monotherapy for Decreasing the Risk of Inflammatory Bowel Disease-Related Complications. J Crohns Colitis 14:1354\u0026ndash;1363. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/ecco-jcc/jjaa050\u003c/span\u003e\u003cspan address=\"10.1093/ecco-jcc/jjaa050\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eColombel JF, Sandborn WJ, Reinisch W et al (2010) Infliximab, Azathioprine, or Combination Therapy for Crohn\u0026rsquo;s Disease. N Engl J Med 362:1383\u0026ndash;1395. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1056/NEJMoa0904492\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa0904492\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKirchgesner J, Lemaitre M, Carrat F et al (2018) Risk of Serious and Opportunistic Infections Associated With Treatment of Inflammatory Bowel Diseases. Gastroenterology 155:337\u0026ndash;346e10. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1053/j.gastro.2018.04.012\u003c/span\u003e\u003cspan address=\"10.1053/j.gastro.2018.04.012\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSingh S, Facciorusso A, Dulai PS et al (2020) Comparative Risk of Serious Infections With Biologic and/or Immunosuppressive Therapy in Patients With Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc 18:69\u0026ndash;81e3. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.cgh.2019.02.044\u003c/span\u003e\u003cspan address=\"10.1016/j.cgh.2019.02.044\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYang S, Yang S, Kwon Jo Y et al (2021) Efficacy and tolerability of infliximab retreatment in patients with inflammatory bowel disease: a systematic review and meta-analysis. Ther Adv Chronic Dis 12:20406223211041927. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1177/20406223211041927\u003c/span\u003e\u003cspan address=\"10.1177/20406223211041927\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTorres J, Boyapati RK, Kennedy NA et al (2015) Systematic Review of Effects of Withdrawal of Immunomodulators or Biologic Agents From Patients With Inflammatory Bowel Disease. Gastroenterology 149:1716\u0026ndash;1730. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1053/j.gastro.2015.08.055\u003c/span\u003e\u003cspan address=\"10.1053/j.gastro.2015.08.055\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKennedy NA, Heap GA, Green HD et al (2019) Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn\u0026rsquo;s disease: a prospective, multicentre, cohort study. Lancet Gastroenterol Hepatol 4:341\u0026ndash;353. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S2468-1253(19)30012-3\u003c/span\u003e\u003cspan address=\"10.1016/S2468-1253(19)30012-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePauwels RWM, van der Woude CJ, Nieboer D et al (2022) Prediction of Relapse After Anti-Tumor Necrosis Factor Cessation in Crohn\u0026rsquo;s Disease: Individual Participant Data Meta-analysis of 1317 Patients From 14 Studies. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc 20:1671\u0026ndash;1686e16. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.cgh.2021.03.037\u003c/span\u003e\u003cspan address=\"10.1016/j.cgh.2021.03.037\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003evan der Valk ME, Mangen M-JJ, Leenders M et al (2014) Healthcare costs of inflammatory bowel disease have shifted from hospitalisation and surgery towards anti-TNFα therapy: results from the COIN study. Gut 63:72\u0026ndash;79. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1136/gutjnl-2012-303376\u003c/span\u003e\u003cspan address=\"10.1136/gutjnl-2012-303376\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChapman TP, Gomes CF, Louis E et al (2020) De-escalation of immunomodulator and biological therapy in inflammatory bowel disease. Lancet Gastroenterol Hepatol 5:63\u0026ndash;79. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S2468-1253(19)30186-4\u003c/span\u003e\u003cspan address=\"10.1016/S2468-1253(19)30186-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDoherty G, Katsanos KH, Burisch J et al (2018) European Crohn\u0026rsquo;s and Colitis Organisation Topical Review on Treatment Withdrawal [\u0026rsquo;Exit Strategies\u0026rsquo;] in Inflammatory Bowel Disease. J Crohns Colitis 12:17\u0026ndash;31. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/ecco-jcc/jjx101\u003c/span\u003e\u003cspan address=\"10.1093/ecco-jcc/jjx101\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-colorectal-disease","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijcd","sideBox":"Learn more about [International Journal of Colorectal Disease](http://link.springer.com/journal/384)","snPcode":"384","submissionUrl":"https://submission.nature.com/new-submission/384/3","title":"International Journal of Colorectal Disease","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Inflammatory Bowel Disease, Tumor Necrosis Factor-alpha, Antagonists and Inhibitors, Meta-Analysis","lastPublishedDoi":"10.21203/rs.3.rs-7842211/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7842211/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eTumor necrosis factor (TNF) antagonists are central to the management of inflammatory bowel disease (IBD), but concerns regarding long-term safety, infection risk, and costs have prompted interest in treatment de-escalation. Whether discontinuing TNF therapy in patients with sustained remission is safe remains uncertain.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003e We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing TNF antagonist withdrawal with continuation in IBD patients in sustained remission. Databases including MEDLINE, Embase, CENTRAL, and ClinicalTrials.gov were searched through July 2025. Eligible trials enrolled adults with Crohn\u0026rsquo;s disease or ulcerative colitis in clinical remission. Primary outcomes were relapse risk and sustained remission. Data were pooled using a random-effects model.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eFour RCTs comprising 485 patients were included. TNF antagonist withdrawal was associated with a significantly higher risk of relapse compared with continuation (RR: 3.00, 95% CI: 1.47\u0026ndash;6.11). Time to relapse was also shorter in the withdrawal group (HR: 5.34, 95% CI: 2.05\u0026ndash;13.92). Sustained clinical remission did not differ significantly between groups (RR: 0.83, 95% CI: 0.55\u0026ndash;1.27). Withdrawal reduced infection risk (RR: 0.47, 95% CI: 0.25\u0026ndash;0.90), while rates of gastrointestinal and serious adverse events were comparable.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eDiscontinuation of TNF antagonists in IBD patients in remission substantially increases the risk and accelerates the timing of relapse, though it lowers infection risk. Careful patient selection and close monitoring are essential if withdrawal is considered.\u003c/p\u003e","manuscriptTitle":"Withdrawal of TNF Antagonists in Patients with Inflammatory Bowel Disease in Remission: A Systematic Review and Meta-analysis of Randomized Controlled Trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-11 17:16:10","doi":"10.21203/rs.3.rs-7842211/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accepted","date":"2025-11-24T16:00:23+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-20T08:00:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"290933174431273569763457530530181875238","date":"2025-11-19T18:38:04+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-19T16:24:09+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-05T02:53:03+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Colorectal Disease","date":"2025-11-03T14:22:46+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-colorectal-disease","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijcd","sideBox":"Learn more about [International Journal of Colorectal Disease](http://link.springer.com/journal/384)","snPcode":"384","submissionUrl":"https://submission.nature.com/new-submission/384/3","title":"International Journal of Colorectal Disease","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"99fcb4f9-26e2-4f0a-8d65-826e4677ab8f","owner":[],"postedDate":"November 11th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-08T16:03:59+00:00","versionOfRecord":{"articleIdentity":"rs-7842211","link":"https://doi.org/10.1007/s00384-025-05047-w","journal":{"identity":"international-journal-of-colorectal-disease","isVorOnly":false,"title":"International Journal of Colorectal Disease"},"publishedOn":"2025-12-02 15:57:27","publishedOnDateReadable":"December 2nd, 2025"},"versionCreatedAt":"2025-11-11 17:16:10","video":"","vorDoi":"10.1007/s00384-025-05047-w","vorDoiUrl":"https://doi.org/10.1007/s00384-025-05047-w","workflowStages":[]},"version":"v1","identity":"rs-7842211","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7842211","identity":"rs-7842211","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}