Selective Drug‐Free Active Surveillance in Ulcerative Colitis: Biomarker‐Guided, Patient‐Centered Approach

ABSTRACT

Ulcerative colitis (UC) is traditionally managed with long‐term 5‐aminosalicylic acid (5‐ASA) administration. However, in real‐world practice, carefully selected low‐risk patients in sustained deep remission may remain stable without continuous therapy. Randomized trials have shown only modest differences in relapse between 5‐ASA and placebo treatment, and real‐world experience indicates that requests to discontinue 5‐ASA during sustained remission are not uncommon. Importantly, symptom‐based assessments can be misleading. Psychosocial factors and a disconnect between symptoms and inflammation, including irritable bowel syndrome overlap, may explain the observed differences. Noninvasive biomarkers, such as fecal calprotectin and serum leucine‐rich alpha‐2 glycoprotein, allow the early detection of subclinical inflammation, supporting the feasibility of a drug‐free active surveillance (DFAS) strategy in selected patients. Biomarker‐guided monitoring can reduce the reliance on colonoscopy and make DFAS more acceptable in practice. Consistent with treat‐to‐target and disease clearance strategies, prioritizing endoscopic and histologic remission, stable biomarkers, and favorable psychosocial conditions may help identify appropriate candidates. A patient‐centered implementation strategy that integrates patient‐reported outcomes, mental health assessments, and shared decision‐making can ensure that DFAS reflects proactive, individualized care rather than therapeutic neglect. Given the growing UC population and disease burden, increasing healthcare costs, and patient preferences to minimize long‐term medication, this review defines the clinical rationale, candidate selection criteria, and a pragmatic biomarker‐guided algorithm for selective DFAS after 5‐ASA in UC and outlines a research agenda to validate safety, feasibility, and cost‐effectiveness. We propose that DFAS be reserved for low‐risk patients under structured surveillance with predefined relapse triggers and rapid rescue pathways.

1. Introduction

Ulcerative colitis (UC) has traditionally been managed under the assumption that continuous maintenance therapy, most often with 5‐aminosalicylic acid (5‐ASA), is essential for all patients to prevent relapse. Current European Crohn's and Colitis Organization (ECCO) and American College of Gastroenterology (ACG) guidelines endorse ongoing maintenance and treat‐to‐target monitoring but provide little explicit guidance on intentional withdrawal [1, 2]. Within this framework, the recommended goals include endoscopic improvement (Mayo Endoscopic Subscore [MES] 0–1) and sustained steroid‐free remission, with objective monitoring that combines fecal calprotectin (FC) and C‐reactive protein (CRP) measurement with endoscopy and, where available, intestinal ultrasound (IUS), rather than symptoms alone [1, 2]. Because symptoms may differ from inflammation and because silent mucosal disease is not uncommon, such objective monitoring should continue during maintenance [1, 2]. However, emerging clinical observations and real‐world trends suggest that this “one‐size‐fits‐all” model may not be universally applicable. A notable proportion of patients remain in remission despite discontinuing treatment, whereas others relapse even with adherence to standard maintenance protocols. These findings imply that UC is not determined by mucosal inflammation alone but rather by a complex interplay of factors [3]. In addition to aberrant immune activation, dysbiosis of the gut microbiota [4], genetic susceptibility [5], and environmental influences such as diet [6], infections [7], and psychosocial stress [8] have been shown to influence the disease course and relapse risk. Furthermore, clinical overlap with functional gastrointestinal disorders such as irritable bowel syndrome (IBS) has been reported [9, 10], with up to one‐third of patients with quiescent IBD experiencing IBS‐like symptoms despite endoscopic remission [11, 12]. These observations highlight that abdominal complaints in remission may not always reflect active inflammation but instead arise from altered gut–brain interactions, including visceral hypersensitivity and dysregulated neurosensory signaling [13].

A recent consensus reframes treatment goals through disease clearance (DC), a composite of clinical, endoscopic, and histologic remission, building on the STRIDE II consensus statement, which prioritizes clinical and endoscopic targets while recognizing histologic healing as an adjunct marker of deeper control [14, 15]. DC has been precisely defined by the IOIBD as simultaneous clinical remission (partial Mayo score 0), endoscopic remission (MES 0), and histologic remission (Nancy index 0) and is associated with improved long‐term outcomes [14, 16], including fewer hospitalizations and surgeries. Nevertheless, DC remains an evolving composite target; however, despite being associated with favorable outcomes, its use as a decision‐making endpoint for treatment de‐escalation or DFAS has not been prospectively validated. Importantly, achieving DC does not equate to a cure and generally still requires maintenance therapy. In this context, we asked whether, in carefully selected low‐risk patients who sustain an MES of 0, histologic remission, and stable biomarkers, structured drug‐free active surveillance under close biomarker‐guided surveillance could be appropriate.

Concurrently, patient preferences are shifting [17]: concerns about medication burden, treatment fatigue, long‐term safety, and healthcare costs have led many individuals, especially younger patients, to voluntarily reduce or stop therapy [18]. In routine practice, gastroenterologists frequently encounter patients in sustained remission who request discontinuation of 5‐ASA; however, clinicians can typically offer only a general warning about relapse risk because evidence to identify candidates who can safely stop therapy remains limited. This unresolved clinical dilemma motivates the present review. Against this backdrop, we introduce selective drug‐free active surveillance (DFAS) to be considered only within clearly defined safety constraints: that is, a structured, biomarker‐guided, patient‐centered monitoring strategy without routine maintenance therapy, with predefined relapse triggers and rapid rescue pathways.

Nevertheless, evidence directly supporting drug‐free 5‐ASA strategies in UC patients remains limited; most data arise from observational cohorts with selection and surveillance biases, heterogeneous remission definitions, and relatively short follow‐up periods. However, randomized head‐to‐head trials are lacking. Accordingly, any drug‐free attempt should be confined to rigorously selected low‐risk patients within predefined biomarker‐guided surveillance and rapid rescue pathways.

In this review, we examine the rationale for a selective DFAS approach in patients with UC; synthesize evidence from clinical trials and observational studies; consider the roles of natural remission, mental health, and real‐world preferences; and outline noninvasive biomarkers for monitoring (biomarkers, IUS (where available), and digital tools). We propose a framework for individualized care that goes beyond pharmacologic persistence toward a more dynamic, patient‐centered model.

2. Evidence From Clinical Trials: A Modest Difference Between an Active Drug and Placebo

The efficacy of 5‐ASA in maintaining remission in patients with UC has been demonstrated in multiple randomized controlled trials (RCTs), although adverse reactions and drug intolerance are not uncommon [19, 20, 21]. Nevertheless, the absolute benefit of 5‐ASA over placebo is relatively modest, raising questions regarding the necessity of continuous therapy for every patient.

A Cochrane meta‐analysis including 1555 patients across eight RCTs revealed that compared with placebo, 5‐ASA significantly reduced the risk of relapse (relapse rates: 37% vs. 52%; relative risk [RR]: 0.68; 95% confidence interval [CI]: 0.61–0.76) [22]. While this finding confirms the therapeutic efficacy of 5‐ASA, two clinically relevant observations emerged: (i) nearly half of the placebo group maintained remission throughout the study period, and (ii) more than one‐third of patients relapsed despite receiving 5‐ASA therapy. Notably, the relatively high proportion of patients who remained in remission despite placebo treatment underscores the heterogeneity of the disease course in patients with UC. Understanding the factors contributing to such high placebo remission rates may not only inform individualized treatment decisions but also help refine the design and interpretation of future clinical trials. However, it should be emphasized that high placebo remission rates in maintenance trials reflect relatively short‐term outcomes under close trial surveillance and do not equate to long‐term drug‐free remission in routine practice.

Recent phase 3 trials of advanced therapies for moderate‐to‐severe UC have also demonstrated that a nonnegligible proportion of patients achieve clinical remission with a placebo, underscoring the heterogeneity of the disease course [23, 24, 25, 26, 27, 28] (Table 1).

TABLE 1.

Recent phase 3 trials of advanced therapies for moderate–severe ulcerative colitis (UC).

References	Year	Study type	Population (n)	Population (key)	Intervention (dose)	Trial/phase	Timepoint	Remission: Drug vs. Placebo	Difference (percentage points)
Sandborn et al. [23]	2023	RCT	433	Mod–severe UC	Etrasimod 2 mg once daily vs. placebo	ELEVATE UC 52/P3	Week 12 (induction)	27% vs. 7%	+20
			433	Mod–severe UC	Etrasimod 2 mg once daily vs. placebo	ELEVATE UC 52/P3	Week 52 (maintenance)	32% vs. 7%	+25
			354	Mod–severe UC	Etrasimod 2 mg once daily vs. placebo	ELEVATE UC 12/P3	Week 12 (induction)	25% vs. 15%	+10
D'Haens et al. [24]	2023	RCT	1281/544	Mod–severe UC	Mirikizumab (IV induction followed by SC maintenance) vs. placebo	LUCENT‐1/−2/P3	Week 12 (induction)	24.2% vs. 13.3%	+10.9
				Mod–severe UC (responders rerand.)	Mirikizumab SC q4w vs. placebo	LUCENT‐2/P3	Week 40 (overall Week52) (maintenance)	49.9% vs. 25.1%	+24.8
Danese et al. [25]	2022	RCT	474 (UC1)	Mod–severe UC	Upadacitinib 45 mg once daily vs. placebo	U‐ACHIEVE Induction (UC1)/P3	Week 8 (induction)	26% vs. 5%	+21
			522 (UC2)	Mod–severe UC	Upadacitinib 45 mg once daily vs. placebo	U‐ACCOMPLISH (UC2)/P3	Week 8 (induction)	34% vs. 4%	+30
Vermeire et al. [26]	2023	RCT	451	Mod–severe UC (responders rerand.)	Upadacitinib 15 mg once daily vs. placebo	U‐ACHIEVE Maintenance/P3	Week 52 (maintenance)	42% vs. 12%	+30
				Mod–severe UC (responders rerand.)	Upadacitinib 30 mg once daily vs. placebo	U‐ACHIEVE Maintenance/P3	Week 52 (maintenance)	52% vs. 12%	+40
Sandborn et al. [27]	2021	RCT	Cohort 1 n = 645, Cohort 2 n = 367; Maintenance randomized n = 457	Mod–severe UC	Ozanimod 0.92 mg once daily vs. placebo	TRUE NORTH/P3	Week 10 (induction)	18.4% vs. 6.0%	+12.4
				Mod–severe UC (responders rerand.)	Ozanimod 0.92 mg once daily vs. placebo	TRUE NORTH/P3	Week 52 (maintenance)	37.0% vs. 18.5%	+18.5
Rubin et al. [28]	2025	RCT	701/568	Mod–severe UC	Guselkumab (IV induction followed by SC q4–8w) vs. placebo	QUASAR/P3	Week 12 (induction)	23% vs. 8%	+15
				Mod–severe UC (responders rerand.)	Guselkumab SC q4w vs. placebo	QUASAR/P3	Week 44 (maintenance)	50% vs. 19%	+31
				Mod–severe UC (responders rerand.)	Guselkumab SC q8w vs. placebo	QUASAR/P3	Week 44 (maintenance)	45% vs. 19%	+26

Note: Clinical remission was defined according to modified or adapted Mayo criteria, which varied across trials. For example, for upadacitinib, the adapted Mayo score was used, whereas for etrasimod (ELEVATE UC 12/52), mirikizumab (LUCENT), ozanimod (TRUE NORTH), and guselkumab (QUASAR) modified Mayo definitions were used (e.g., a stool frequency of 0–1 with a ≥ 1‐point decrease from baseline, a rectal bleeding score of 0, and an endoscopic subscore of 0–1 without friability). The study designs also differed: the ELEVATE UC 52 study used a treat‐through approach, whereas the LUCENT‐2, U‐ACHIEVE Maintenance, TRUE NORTH, and QUASAR trials rerandomized induction responders for the maintenance phase. Population (n) refers to the primary analysis cohort reported in each publication (either the overall induction population or the rerandomized maintenance population); patient numbers in each arm follow the original trial reports. Differences are expressed as percentage points.

Abbreviations: IV, intravenous; P3, phase 3; q4w, every 4 weeks; q8w, every 8 weeks; RCT, randomized control trial; rerand, rerandomized; SC, subcutaneous.

These findings indicate that the risk of relapse is influenced by factors beyond pharmacologic treatment, including the natural history of the disease, genetic susceptibility, environmental exposure, and psychosocial influences. Notably, recent studies have highlighted the impact of psychological stress on UC activity, linking mental health status to flare occurrence and sustained remission [29, 30, 31].

Taken together, these data challenge the assumption that indefinite maintenance therapy benefits all patients with UC equally. The existence of a potentially self‐limiting or quiescent disease phenotype suggests that individualized treatment approaches may be appropriate, providing the possibility of a carefully monitored selective DFAS strategy in well‐defined patient subgroups with a favorable prognosis.

3. Natural Remission and Sustained Drug‐Free Status in UC: A Neglected Subgroup

Although UC is traditionally regarded as a lifelong relapsing condition requiring continuous medical therapy, accumulating evidence indicates that a subset of patients can maintain long‐term remission without pharmacological maintenance. This subgroup, often overlooked in clinical practice, may represent individuals with a naturally mild disease course.

Observational population‐based cohorts have consistently reported drug‐free remission in a small minority of patients. In a prospective Norwegian cohort, approximately 10%–15% of patients sustained remission for more than 5 years without maintenance therapy [32]. Similar proportions (5%–15%) have been observed in other cohorts despite the absence of ongoing treatment [33, 34]. Real‐world data further support these findings; a nationwide retrospective study from Israel revealed no significant difference in the risk of biologic initiation or colectomy between patients with mild UC managed without maintenance therapy and those treated with 5‐ASA [35].

In routine practice, unsupervised 5‐ASA discontinuation or treatment gaps occur, often driven by patients' perceptions of stability, treatment fatigue, or practical considerations. Notably, many of these individuals remain relapse‐free for extended periods. In a 2023 Japanese multicenter survey, nearly 40% of patients expressed a preference for dose reduction or discontinuation of 5‐ASA, even when the risk of relapse was acknowledged [17]. Similarly, a UK study reported that more than 75% of patients aged 18–24 years discontinued 5‐ASA within 1 year of initiation, with many maintaining long‐term stability thereafter [18].

Although randomized trials explicitly evaluating drug‐free management are lacking, these data underscore the heterogeneity of UC and highlight the existence of a low‐risk, treatment‐independent phenotype. Future research should aim to identify biomarkers and endoscopic and psychosocial predictors of sustained drug‐free remission to enable safe patient stratification for de‐escalation or selective DFAS strategies.

4. Psychosocial Factors and Symptom–Inflammation Disconnect

UC outcomes are influenced not only by mucosal inflammation but also by psychosocial factors that affect symptom perception, adherence, and follow‐up. In a filgotinib trial, early improvement in mental health was independently associated with sustained clinical, endoscopic, and histologic remission [29]. In a Japanese multicenter study, many patients reported psychological stress as a trigger for flares, and depressive symptoms were more prevalent during active disease [31]. These data support considering psychosocial readiness as part of shared decision‐making when discussing selective DFAS.

Importantly, patient‐reported symptoms do not always reflect objective inflammatory activity. IBS overlap and functional gastrointestinal symptoms are common even in quiescent UC patients [36, 37] and may be associated with impaired quality of life and heightened anxiety/depression [36]. Thus, symptoms alone are an imperfect trigger for treatment escalation or reinitiation during DFAS.

In the DFAS framework, this symptom–inflammation disconnect reinforces the need for objective, trigger‐based monitoring. Persistent symptoms despite biomarker and endoscopic remission should prompt evaluation for functional overlap rather than automatic inflammatory relapse, whereas biomarker elevation or clinical change should trigger timely reassessment and rapid rescue pathways.

5. Real‐World Practice: Patient Preferences, Nonadherence, and Discontinuation

Although clinical guidelines emphasize the importance of continuous maintenance therapy for UC [1, 2, 38], real‐world practice often diverges considerably from these recommendations. In routine outpatient care, gastroenterologists usually receive requests to discontinue 5‐ASA during sustained remission. Some patients may then voluntarily taper or discontinue therapy or disengage from follow‐up, sometimes regardless of medical advice, resulting in unmonitored drug‐free intervals (“invisible” nonmaintenance therapy) that differ from our proposed DFAS strategies, which are intentionally supervised and trigger‐based.

Recent surveys have illustrated these trends. In a multicenter study in Japan, nearly 40% of patients expressed a preference for dose reduction or discontinuation of 5‐ASA, even when they were informed of the risk of relapse. Strikingly, more than 85% of physicians reported using serum or fecal biomarkers to monitor patients after de‐escalation, underscoring the clinical demand and practical feasibility of such strategies [17]. Similar behavior has been observed in other regions: in a large retrospective cohort from the UK, more than 75% of patients aged 18–24 years discontinued 5‐ASA within 1 year of initiation, highlighting both adherence challenges and generational differences in treatment expectations [18]. Data from Israel further reinforce these observations: among patients with mild UC, outcomes in terms of biologic initiation and colectomy were similar between those managed with no maintenance therapy (NMT; no routine maintenance drugs) and those maintained on 5‐ASA [35]. Notably, NMT reflects the passive absence of therapy and differs from our proposed DFAS approach, which involves structured, biomarker‐guided surveillance with predefined relapse triggers and rapid rescue pathways.

These findings imply that not all patients derive equal benefit from routine maintenance and that clinical practice is shaped as much by patient attitudes and lived experiences as by disease severity or guideline adherence. Decisions to stop medication are often influenced not only by symptom status but also by treatment fatigue, side effect concerns, financial burden, and the psychological readiness of the patient. In some instances, patients discontinue therapy despite clinical advice or without informing their clinicians, creating a phenomenon of “invisible NMT,” which remains underrecognized in long‐term care.

Collectively, these data highlight the need to formally acknowledge and study drug‐free management strategies that already exist in practice. The incorporation of shared decision‐making, guided by both objective risk stratification and patient preferences, may help bridge the gap between idealized treatment protocols and real‐world patient behavior. From a health‐economic perspective, these implications are particularly relevant in Japan, where the number of patients with UC continues to steadily increase [39]. A large claims‐based study comprising more than 15 000 UC patients reported mean monthly medical costs of approximately ¥76 000, with suboptimal therapy patterns (e.g., prolonged or cyclical corticosteroid use) significantly increasing both resource utilization and costs [40]. Epidemiological data further revealed a dramatic increase in the prevalence of UC from 5 per 100 000 in 2010 to 98 per 100 000 in 2019 [40]. Moreover, UC is associated with substantial indirect costs in Japan, including impaired work productivity and reduced quality of life [41]. Given the lifelong nature of the disease, the indiscriminate continuation of 5‐ASA therapy in all patients imposes a substantial cumulative burden on both the healthcare system and individuals. Identifying low‐risk patients who can be safely managed without maintenance therapy may therefore reduce unnecessary drug expenditures and optimize the allocation of limited healthcare resources, while maintaining the quality of care. Beyond patient preferences, payer policies and test reimbursement materially shape both maintenance choices and the feasibility of biomarker‐guided DFAS.

6. Health System and Cost Considerations Across Regions

In addition to biological risk and patient preferences, payer policies and test reimbursements determine whether DFAS can be safely operationalized. Across regions, costs and reimbursements materially shape maintenance choices and the practicality of biomarker‐guided surveillance. In a physician survey across eight Asian territories (Hong Kong, Taiwan, Singapore, Thailand, Malaysia, the Philippines, Vietnam, and Indonesia), fecal calprotectin was not reimbursed in any territory (Aug 2021), whereas colonoscopy and CRP testing were generally reimbursed. In contrast, fecal calprotectin testing is currently reimbursed in Japan. In terms of this reimbursement background, “treatment‐free remission” and “long‐term cost savings” ranked higher in lower‐ and upper‐middle‐income settings than in high‐income ones [42]. Preferences also varied by affordability and access: MMX formulations were favored in high‐income economies, whereas multiple daily dosing was more common where newer preparations were scarce [42]. In contrast, Japan's public subsidies reduce cost sensitivity and enable more proactive monitoring, including routine endoscopy and the use of FC and serum LRG testing, even during maintenance. These cross‐country differences imply that selective DFAS, if attempted, must be coupled with locally feasible monitoring budgets and payer policies, not just biological risk stratification [43].

7. Toward a Selective Drug‐Free Active Surveillance (DFAS) Strategy

Given the growing recognition of heterogeneity in the clinical course of UC, a uniform “one‐size‐fits‐all” approach to maintenance therapy may be inappropriate. Evidence from spontaneous remission, the modest absolute benefit of 5‐ASA over placebo, and real‐world patterns of treatment discontinuation collectively support the feasibility of a selective DFAS strategy in carefully chosen patients with UC. In this sense, DFAS is intended to replace unmonitored “invisible” drug‐free intervals with an intentionally supervised, risk‐mitigated pathway, thereby potentially improving safety compared with unsupervised discontinuation.

7.1. Identifying Candidates for DFAS

Candidates most suitable for DFAS are likely to represent a low‐risk phenotype characterized by sustained quiescence and minimal inflammatory burden. The following features, supported by the literature and clinical experience, may help define such individuals.

• Endoscopic and histologic remission: A Mayo Endoscopic Subscore (MES) of 0 is essential for remission. When feasible, histologic remission should be achieved using a validated index (e.g., Nancy histologic index of 0 or RHI ≤ 3), as residual microscopic activity predicts relapse; patients with an MES of 1 have a substantially higher risk of relapse and are generally unsuitable for de‐escalation [44].

• Biomarker stability: Normal FC and/or serum leucine‐rich alpha‐2 glycoprotein (LRG) levels indicate mucosal and histological healing [45, 46].

• Mild disease phenotype: A history of only mild disease activity without prior use of corticosteroids, immunomodulators, or biologics.

• Psychological stability: The absence of significant anxiety, depression, or perceived stress, such as mental health status, independently influences relapse risk and adherence [31].

• Patient preference: A clear desire to reduce the medication burden, coupled with a willingness to comply with structured monitoring.

• Colorectal cancer (CRC) risk and chemoprevention: Potential chemopreventive considerations of mesalazine should be acknowledged when contemplating complete withdrawal. The 2025 BSG guidelines suggest that nonsulfasalazine mesalazine used as a UC monotherapy may be chemopreventive, but any additional chemopreventive benefit when mesalazine is not required for inflammatory control (e.g., during advanced therapies) remains unclear; therefore, DFAS should generally be avoided in patients at increased risk of IBD‐CRC, and standard dysplasia surveillance should continue [47].

While no single factor is sufficient, the combination of these criteria may delineate a “treatment‐independent” UC phenotype suitable for supervised drug‐free observation.

7.2. Risk Stratification and Monitoring

Any attempt to discontinue maintenance therapy should be embedded within a structured surveillance program aimed at the early detection of subclinical inflammation. To minimize burden, the surveillance intensity should be risk‐adaptive and trigger‐based and aligned with the treat‐to‐target objective monitoring used during maintenance. Key strategies include: (i) noninvasive biomarkers (FC preferred including home‐based testing [48, 49] where available; LRG/CRP as alternatives) at predefined testing intervals (e.g., every 3–6 months initially), with de‐escalation (e.g., extending to 6–12 months) when biomarkers remain stable; (ii) endoscopic surveillance: prioritized by standard dysplasia surveillance schedules and triggered by biomarker elevation or clinical change; (iii) patient‐reported outcome measures (PROMs): regular assessment of subtle symptoms and psychological distress, with predefined relapse triggers and rapid rescue pathways; and (iv) implementation streamlining: digital health approaches (e.g., home‐based FC testing where available, remote symptom/ePRO monitoring, and patient‐initiated follow‐up) may enable risk‐adaptive triage and reduce unnecessary visits and procedures while maintaining timely escalation when objective markers increase [50].

Such proactive monitoring allows for timely reintroduction of therapy, reducing the risk of severe flare‐ups while minimizing unnecessary drug exposure.

7.3. Shared Decision‐Making in DFAS

The implementation of DFAS should not be a unilateral decision by the physician. Instead, it must be grounded in shared decision‐making (SDM), in which the potential benefits and risks are carefully weighed against the following: (i) the patient's values, life circumstances, and preferences; (ii) their clinical history and objective risk indicators; and (iii) the feasibility of close follow‐up and adherence to monitoring should be assessed in future studies.

Patients should be explicitly informed that DFAS is not equivalent to therapeutic neglect but rather an intentional, data‐driven, and closely monitored strategy appropriate for selected low‐risk contexts. In practice, DFAS candidates can be divided into patients who spontaneously request drug reduction (“voluntary DFAS”) and those for whom physicians may cautiously propose DFAS after comprehensive risk assessment (“advised DFAS”). In both scenarios, SDM requires explicit discussion of relapse risk, the nonstandard nature of DFAS, and the need for strict adherence to the surveillance schedule. How SDM for DFAS can be operationalized in routine care and its impact on patient‐centered outcomes should be addressed in future prospective studies.

8. Monitoring Without Maintenance: The Role of Biomarkers and Endoscopy

A prerequisite for implementing a selective DFAS strategy for UC is the ability to safely monitor disease activity and detect early signs of relapse. Although endoscopy has long been the gold standard for evaluating mucosal healing, its invasiveness, cost, and limited feasibility for long‐term follow‐up highlight the need for reliable noninvasive biomarkers as practical alternatives in DFAS frameworks (Table 2).

TABLE 2.

Key monitoring methods for patients with remission from Ulcerative Colitis (UC).

Tool	Purpose	Frequency	Advantages	Limitations
Symptom evaluation (clinical assessment, PROs)	Capture patient‐reported outcomes, early signs of relapse	Every visit, ongoing	Simple, patient‐centered, captures QoL	Subjective, may miss silent inflammation
Biomarkers: CRP	Objective noninvasive screening, systemic inflammation	Every 3–6 months (remission), with flares	Widely available, inexpensive, dynamic marker of systemic inflammation	May be nonspecific and often insensitive to mucosal inflammation in UC
Biomarkers: LRG	Sensitive detection of intestinal inflammation; secreted locally in response to multiple cytokines (IL‐6, IL‐1β, IL‐22, TNF)	Every 3–6 months or as an alternative to stool tests	Serum‐based, more sensitive than CRP for subclinical mucosal inflammation, useful when stool tests are not feasible	New marker, cutoffs still being validated, limited availability outside Japan
Biomarkers: Fecal calprotectin	Gold standard noninvasive marker of neutrophilic intestinal inflammation	Every 3–6 months (remission), more often with symptoms	Strong correlation with endoscopic/histologic activity, predictive of relapse	Requires stool collection, variability, and patient acceptance issues
Colonoscopy	Gold standard, mucosal healing	At diagnosis, after flare, periodic	Direct visualization	Invasive, cost, time
IUS/MRI	Assess deep/subclinical inflammation	Every 3–6 months (active), as indicated	Noninvasive, repeatable	Cost (MRI), operator dependence (IUS)
Wearables/Home monitoring (apps, devices, patient portals)	Experimental use for flare prediction, ongoing self‐monitoring	Ongoing/self‐monitoring	Convenience, patient empowerment, and potential for early detection of relapse	Early stage, not standard of care, requires validation and adherence

Note: Monitoring UC (ulcerative colitis) requires a personalized approach using a combination of these modalities to optimize care and health outcomes for individuals with UC.

Abbreviations: IUS, intestinal ultrasound; LRG, leucine‐rich α2‐glycoprotein; PROs, patient‐reported outcomes.

8.1. Fecal Calprotectin (FC): The Noninvasive Benchmark

FC is the most validated surrogate marker of neutrophilic intestinal inflammation. Multiple prospective studies have confirmed its correlation with both endoscopic and histological disease activity, and FC reliably predicts relapse in patients in clinical remission, often increasing weeks before the onset of symptoms. In a prospective trial, Piñero et al. demonstrated that adjusting mesalazine dosing according to FC levels significantly reduced relapse risk and permitted safe treatment de‐escalation in selected patients [45]. Thus, FC serves not only as a monitoring tool but also as a guide for personalized therapeutic decisions, making it particularly relevant for patients with DFAS.

8.2. Leucine‐Rich Alpha‐2 Glycoprotein (LRG): An Emerging Serum Marker

LRG has recently gained attention as a promising serum marker of inflammatory activity in patients with UC. Unlike CRP, LRG is locally produced by inflamed intestinal tissue in response to cytokines, including IL‐6, IL‐1β, IL‐22, and TNF, thereby increasing the sensitivity to detect subclinical inflammation [46, 51]. A Japanese multicenter study reported that LRG levels outperformed both CRP levels and FC levels at several time points during biological therapy, underscoring its value as a practical, noninvasive surveillance tool, especially for patients who are unwilling or unable to provide stool samples.

8.3. Endoscopy: Still Indispensable but in Selected Contexts

Despite the appeal of noninvasive markers, endoscopy remains essential in specific situations, such as in patients with prior dysplasia, complicated disease courses, or inconclusive biomarker findings. However, in the context of DFAS, the frequency of endoscopy may be reduced. A national survey in Japan revealed that nearly half of the physicians considered colonoscopy intervals of up to 2 years acceptable for low‐risk patients, which is consistent with dysplasia surveillance schedules and with earlier reassessment triggered by biomarker elevation or clinical symptoms [52]. These findings support a risk‐adapted biomarker‐guided approach to surveillance in drug‐free patients.

8.4. Toward a Real‐World Monitoring Algorithm

On the basis of the current evidence, a pragmatic monitoring strategy for patients managed without maintenance therapy may include the following: (i) FC testing every 3–6 months (cutoff ~150–250 μg/g, adjusted to baseline); (ii) serum LRG or CRP measurement every 3–6 months if stool testing is not feasible; (iii) colonoscopy per dysplasia surveillance schedule; additional procedures triggered by biomarker elevation or symptom recurrence; and (iv) regular patient‐reported outcome measures (PROMs) to capture subtle symptomatic and psychological changes.

9. Future Perspectives and Research Directions

While emerging evidence supports the feasibility of a selective DFAS approach for UC, robust data from prospective trials are lacking. Most current findings are derived from observational studies, retrospective analyses, and real‐world patient behaviors. High‐quality RCTs are essential for formally incorporating DFAS into treatment algorithms.

9.1. Dedicated Randomized Controlled Trials

No RCT has been specifically designed to compare DFAS with standard maintenance therapy in low‐risk UC patients. Carefully stratified trials are needed to evaluate relapse rates, quality of life, healthcare resource utilization, and long‐term safety across strategies such as (i) continuous 5‐ASA maintenance; (ii) tapered or intermittent therapy; and (iii) structured DFAS with biomarker‐guided surveillance.

Such studies should employ stringent eligibility criteria (e.g., MES of 0, low FC/LRG levels) and standardized monitoring protocols. Without these data, clinicians are unlikely to adopt DFAS despite increasing real‐world evidence.

9.2. Patient‐Reported Outcomes and Longitudinal Cohorts

Future research should also incorporate patient‐reported outcome measures (PROMs) that capture quality of life, treatment burden, psychological distress, and patient preference. These dimensions are especially relevant in DFAS, where goals extend beyond controlling inflammation to the functional and psychosocial well‐being of the patients. Longitudinal studies following patients who voluntarily discontinue maintenance therapy, whether monitored or unmonitored, could provide critical insights into real‐world risks, protective factors, and predictors of sustained drug‐free remission.

9.3. Toward Individualized Treatment Algorithms

Ultimately, the future of UC management lies in personalized algorithms that align treatment intensity with disease risk, patient values, and psychosocial context. DFAS should not be regarded as a “lesser” approach but as a strategically chosen, actively monitored alternative appropriate for a well‐defined subgroup of patients. Achieving this paradigm shift will require moving from treating only the disease to treating the whole person living with UC.

10. Extension to Advanced Therapy De‐Escalation (Speculative)

Although this review focuses on DFAS after 5‐ASA treatment, the same risk‐mitigated concept may be more compelling when applied to the de‐escalation of advanced therapies, where drug costs, cumulative toxicity, and monitoring burdens are substantially higher. In this setting, structured withdrawal with objective monitoring and predefined rescue pathways could provide a pragmatic framework to balance sustained remission against long‐term treatment burden. However, evidence for safe de‐escalation strategies remains limited and heterogeneous; therefore, prospective studies are needed to define eligibility, monitoring intensity, and rescue thresholds.

11. Conclusion

The conventional paradigm of continuous maintenance therapy for UC has long been regarded as the standard of care. However, the accumulation of clinical, biological, and psychosocial evidence indicates that this approach may not be universally applicable. A meaningful subgroup of patients—defined by sustained mucosal healing, minimal inflammatory activity, psychological stability, and a clear preference for reducing treatment—appears capable of maintaining remission without ongoing pharmacologic intervention.

In this review, we have summarized the rationale for a selective DFAS strategy, supported by evidence from randomized trials, observational cohorts, real‐world practice, and emerging biomarker‐guided monitoring. Crucially, DFAS should not be considered a passive withdrawal of therapy but rather a deliberate, actively monitored option pursued only in carefully selected patients through shared decision‐making.

Adopting such an approach has the potential to reduce treatment burden, enhance quality of life, and optimize healthcare resource utilization in the face of a steadily increasing UC population. As IBD management increasingly embraces the principles of personalized medicine, selective DFAS should be viewed not as a lesser alternative but as a pragmatic, patient‐centered strategy that deserves further prospective validation and thoughtful incorporation into future clinical guidelines.

Funding

The authors have nothing to report.

Ethics Statement

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.