Achieving deep remission, encompassing clinical, endoscopic, and biological remission, is the goal in managing Crohn's disease (CD). The role of histological remission (HR) remains unclear. This study aimed to examine the impact of histological inflammation on clinical relapse risk in CD and explore the relationship between histology, endoscopic scores, and biomarkers.

Patients from the prospective STORI (Stable Remission on Combined Therapy with Immunosuppressors) cohort underwent ileocolonoscopy with Crohn's Disease Endoscopic Index of Severity calculation and 2 biopsies from the most inflamed or previously inflamed areas. Histological scores (Robarts, Geboes, modified Geboes, Nancy, and IBD-DCA) were determined by 2 independent pathologists in a central reading process. Histological remission was defined by specific score thresholds. Clinical relapse, defined by Crohn's Disease Activity Index (CDAI) > 250 or a CDAI increase of 70 points over 2 weeks, was monitored for at least 1 year.

Out of 115 patients included in STORI, 160 biopsies (44 ileal and 116 colonic) from 76 patients were analyzed. Histological remission rates were 46% (Nancy), 55% (Robarts), 61% (Geboes), and 41% (IBD-DCA). During follow-up, 35 patients (46%) experienced a clinical relapse: 37% with HR and 56% without, based on the Nancy score. Among the mucosal healing subgroup (45 patients), 34% with HR, and 44% without relapsed (p = 0.18). Histological scores did not predict clinical relapse. Only fecal calprotectin was a significant predictor in multivariate analysis (p = 0.029).

Despite correlations with endoscopy and biomarkers, histological scores did not predict clinical relapse in CD patients in remission. Thus, these scores are not recommended for clinical practice to assess relapse risk in CD.

Primary objectives: to compare the rates of sustained clinical remission at 12 months in patients treated with antitumour necrosis factor (anti-TNF) and immunomodulators who withdraw anti-TNF treatment versus those who maintain it.

to evaluate the effect of anti-TNF withdrawal on relapse-free time, endoscopic and radiological activity, safety, quality of life and work productivity; and to identify predictive factors for relapse.

Prospective, quadruple-blind, multicentre, randomised, controlled trial. Patients with ulcerative colitis or Crohn's disease in clinical remission for >6 months and absence of severe endoscopic (and radiological in Crohn's disease) lesions were randomised to maintain anti-TNF treatment (maintenance arm (MA)) or to withdraw it (withdrawal arm (WA)). All patients maintained immunomodulators. Patients were followed-up until month 12 or up to clinical relapse.

One-hundred forty patients were randomised: 70 were allocated to the MA and 70 to the WA. The proportion of patients with sustained clinical remission at 12 months was similar in the MA and WA: 59/70 (84%), 95% CI=74% to 92% versus 53/70 (76%), 95% CI=64% to 85%. The proportion of patients with significant endoscopic lesions at the end of follow-up was 8.5% in the MA and 19% in the WA (p=0.1); a higher proportion of patients had faecal calprotectin >250 µg/g at the end of follow-up in the WA (p=0.01). The same percentage of patients in both groups had at least one adverse event (69%). The proportion of patients with serious adverse events was also similar in both groups (4% in MA vs 7% in WA).

Anti-TNF withdrawal in selected patients with IBD in clinical, endoscopic and radiological remission has no impact on sustained clinical remission at 1 year although objective markers of activity were higher in patients who withdrew treatment.

https://www.clinicaltrialsregister.eu/ctr-search/search?query=2015-001410-10 https://clinicaltrials.gov/study/NCT02994836.

The Groupe d'Etude sur les Affections Inflammatoires Digestives (GETAID) was founded in Paris in 1983 by Professor Robert Modigliani and colleagues. From the beginning, the aim of this international (France, Belgium, and Switzerland), multicenter, French-speaking group was to address clinical questions raised by patients or physicians in their daily practice or the inflammatory bowel disease community, by focusing on clinical research on treatments through randomized controlled trials, prospective cohorts, and cross-sectional studies, quantifying the severity of various facets of the disease when necessary for these studies. This very innovative approach has contributed to the advancement of knowledge in inflammatory bowel diseases by publishing more than 120 original articles in peer-reviewed journals throughout the GETAID's 40-year history, most of them in top publications in gastroenterology and hepatology journals. In this paper, we will see what GETAID's contribution has been over the last 4 decades and review the reasons for its success and forthcoming challenges.

Inflammatory bowel diseases (IBD) including Crohn's disease (CD) and ulcerative colitis (UC) are chronic, relapsing conditions characterized by dysregulated immune responses and persistent intestinal inflammation. This review aims to examine new potential therapeutic targets in IBD starting from the STRIDE-II statements. Key targets now include clinical remission, endoscopic remission, and biomarker normalization (such as C-reactive protein and fecal calprotectin). Moreover, histologic remission, transmural remission, and in the future molecular targets are emerging as important indicators of sustained disease control. The treatment goals for inflammatory bowel disease are varied: to relieve symptoms, prevent permanent intestinal damage, promote inflammation remission, and minimize complications. Consequently, the therapeutic targets have evolved to become broader and more ambitious. Integrating these advanced therapeutic targets has the potential to redefine IBD management by promoting deeper disease control and improved patient outcomes. Further research is essential to validate these strategies and optimize their clinical implementation.

The introduction of tumor necrosis factor inhibitors has led to a paradigm shift in the management of inflammatory bowel disease (IBD). The subsequent introduction of both anti-integrins and cytokine blockers has since expanded the biologic armamentarium. However, immunogenicity, defined as the production of anti-drug antibodies (ADAs) to the prescribed biopharmaceutical, means a significant fraction of patients exposed to biologic agents will experience a secondary loss of response to one or more of the drugs. In clinical settings, immunogenicity may be caused by several factors, both patient related (e.g., underlying chronic disease, systemic immune burden, including previous biologic therapy failure, and [epi]genetic background) and treatment related (e.g., dose and administration regimens, drug physical structure, photostability, temperature, and agitation). Here, we outline these elements in detail to enhance biopharmaceutical delivery and therapy for patients with IBD. Moreover, concurrent immunomodulator medication may reduce the risks of ADA generation, especially when using the chimeric drug infliximab. Summarizing the latest developments and knowledge in the field, this review aims to provide strategies to prevent ADA production and information on managing non-responsiveness or loss of response to biologics. Better understanding of the molecular mechanisms underlying the formation of ADAs and the critical factors influencing the immunogenicity of biopharmaceuticals may lead to improved health outcomes in the IBD community that may benefit both the individual patient and society through lower healthcare expenses.

Standardized evaluation of endoscopic disease activity using valid, responsive and reliable instruments is crucial for optimizing the efficiency of clinical trials with therapeutic agents for Crohn's disease (CD). Achieving endoscopic remission and/or mucosal healing is associated with improved long-term outcomes, making it an important treatment goal.

Several endoscopic indices have been used over the past two decades, though they lack complete validation. The Crohn's Disease Endoscopic Index of Severity (CDEIS) and Simple Endoscopic Score for Crohn's Disease (SES-CD) demonstrate fair reliability and responsiveness to treatment. The CDEIS is rather complex and time-consuming, and both endoscopic indices are prone to variability. The Lewis Score and Capsule Endoscopy CD Activity Index (CECDAI) provide useful alternative instruments using video capsule endoscopy, but they need further validation. The Rutgeerts score predicts post-surgical recurrence but lacks evaluation for follow-up.

While recent guidelines emphasize co-primary clinical and endoscopic endpoints to improve trial effectiveness, these are typically based on expert consensus rather than empirical data. We advocate to use SES-CD as the preferred endoscopic index given its simplicity, strong correlation with CDEIS, and treatment responsiveness. Future research should focus on establishing clinically relevant cutoff values for endoscopic response and endoscopic remission in CD trials, including post-operative settings.

In patients with Crohn's disease (CD) on combination therapy (infliximab and immunosuppressant) and stopping infliximab (cohort from the study of infliximab diSconTinuation in CrOhn's disease patients in stable Remission on combined therapy with Immunosuppressors (STORI)), the risk of short-term (≤6 months) and mid/long-term relapse (>6 months) was associated with distinct blood protein profiles. Our aim was to test the external validity of this finding in the SPARE cohort (A proSpective Randomized Controlled Trial comParing infliximAb-antimetabolites Combination Therapy to Anti-metabolites monotheRapy and Infliximab monothErapy in Crohn's Disease Patients in Sustained Steroid-free Remission on Combination Therapy).

In SPARE, patients with CD in sustained steroid-free clinical remission and on combination therapy were randomly allocated to three arms: continuing combination therapy, stopping infliximab or stopping immunosuppressant. In the baseline serum of the STORI and SPARE (arm stopping infliximab) cohorts, we studied 202 immune-related proteins. The proteins associated with time to relapse (univariable Cox model) were compared between STORI and SPARE. The discriminative ability of biomarkers (individually and combined in pairs) was evaluated by the c-statistic (concordance analysis) which was compared with C-reactive protein (CRP), faecal calprotectin and a previously validated model (CEASE).

In STORI and SPARE, distinct blood protein profiles were associated with the risk of short-term (eg, high level: CRP, haptoglobin, interleukin-6, C-type lectin domain family 4 member C) and mid/long-term relapse (eg, low level: Fms-related tyrosine kinase 3 ligand, kallistatin, fibroblast growth factor 2). At external validation, the top 10 biomarker pairs showed a higher c-statistic than the CEASE model, CRP and faecal calprotectin in predicting short-term (0.76-0.80 vs 0.74 vs 0.71 vs 0.69, respectively) and mid/long-term relapse (0.66-0.68 vs 0.61 vs 0.52 vs 0.59, respectively).

In patients with CD stopping infliximab, we confirm that the risk of short-term and mid/long-term relapse is associated with distinct blood protein profiles showing the potential to guide infliximab withdrawal.

NCT00571337 and NCT02177071.

Biologics are important therapeutic agents for pediatric Crohn's disease. Discontinuation of biologics is known to increase the relapse rate up to 71.4% in these patients; however, their long-term use increases the risk of opportunistic infections and causes economic burden and psychological fatigue. Therefore, taking a drug holiday is meaningful, even if the biologics cannot be completely discontinued. This study aimed to analyze the risk factors affecting relapse after discontinuation of biologics in children with Crohn's disease.

We retrospectively reviewed the data of 435 children with Crohn's disease who visited a single health center between March 2013 and March 2021. Subsequently, we analyzed data from the patients who discontinued biologics after deep remission.

Among the enrolled patients, 388 were followed up for ≥2 years, and of these, 357 were administered biologics. A total of 103 patients discontinued biologics after deep remission, subsequently 31 maintained remission and 72 relapsed. The shorter the duration of biologic treatment (odds ratio of 0.444, P = 0.029), the higher the ESR (odds ratio of 1.294, P = 0.009) and fecal calprotectin (odds ratio of 1.010, P = 0.032), and the less histological remission at the time of discontinuation of biologics (odds ratio of 0.119, P = 0.026), the greater the risk of relapse after discontinuation of biologics.

We identified factors associated with relapse after discontinuation of biologics. The results suggest that biologics can be discontinued in the absence of these factors after deep remission. However, because the relapse rate may increase after the discontinuation of biologics, close monitoring is important, and if necessary, re-administration of biologics should be actively considered.

No models predict future outcomes in inflammatory bowel disease (IBD) patients receiving maintenance infliximab therapy. We created a predictive model for unfavorable outcomes.

Adult patients with IBD receiving maintenance infliximab therapy at 2 centers with matched serum infliximab concentrations and blinded histologic scores (Robarts Histopathologic Index [RHI]) were included. The primary endpoint was an unfavorable outcome of active objective inflammation or need for IBD-related surgery or hospitalization at 6-18 months follow-up. Internal variables were identified using univariable analyses, modeling used multivariable analysis, and performance was assessed (area under receiver-operating curve [AUC]) and externally validated.

In 81 patients, 40.7% developed unfavorable outcomes at follow-up. Infliximab concentration <9.3 µg/mL (odds ratio [OR] 5.3, P = .001) and RHI > 12 (OR 3.4, P = .03) were the only factors associated with developing the primary unfavorable outcome. A prediction score assigning 1 point to each variable had good discrimination and performed similarly on internal (AUC 0.71) and external (AUC 0.73) cohorts. The risk of primary unfavorable outcomes in internal and external cohorts, respectively, was 23% and 15% for a score of 0, 46% and 50% for a score of 1, and 100% and 75% for a score of 2. Infliximab concentration alone performed similar to the 2-predictor model in internal (AUC 0.65, P = .5 vs. 2-predictor model) and external (AUC 0.70, P = .9, vs. 2-predictor model) cohorts.

Using unbiased variable selection, a 2-predictor model using infliximab concentrations and histology identified IBD patients on maintenance infliximab therapy at high risk of future unfavorable outcomes. For practical applicability, infliximab concentrations alone performed similarly well.

Medication holidays in inflammatory bowel disease (IBD) offer a potential means to balance disease management, costs, and quality of life. This concept is increasingly relevant in light of the chronic nature of IBD, the cumulative side effects associated with long-term pharmacotherapy, and the evolving treatment landscape that now includes a large armamentarium of effective induction, maintenance, and rescue therapies paired with disease monitoring tools that enable early intervention.

This review critically examines the rationale, implementation, and risks of medication holidays in IBD. Recent evidence is reviewed to help guide the risks of relapse involved with cessation of therapy. The selection criteria for patients, the necessary monitoring protocols, and strategies for managing potential relapses are outlined.

Despite the potential benefits, medication holidays in IBD involve significant risks and require careful patient selection and active management. Current research highlights a need for improved predictive models and a deeper understanding of patient-specific outcomes and consequences. The future of medication holidays will depend heavily on advancements in noninvasive monitoring technologies and more personalized approaches to therapy. Ultimately, establishing clearer guidelines for safely conducting medication holidays will be crucial in integrating this strategy into routine clinical practice.

Combination therapy with an immunomodulator (IMM) and an anti-TNF is commonly recommended in Crohn's disease (CD) and ulcerative colitis (UC) patients. However, little is known about relapse rates after therapeutic de-escalation. This study aimed to evaluate the risk of relapse in a cohort of UC and CD patients with long-standing clinical remission after discontinuation of IMM or anti-TNF and to identify predictive factors for relapse.

This retrospective study included patients with UC or CD on combination therapy and clinical remission for at least 6 months. IMM or anti-TNF was stopped upon physician decision. Primary objective was to evaluate the relapse rates after discontinuation of IMM or anti-TNF and to analyze predictors of relapse.

The study included 88 patients, 48 patients (54.5%) discontinued IMM and 40 (45.5%) anti-TNF. During follow-up, relapse rates were 16.7% and 52.5% in the IMM discontinuation group and anti-TNF discontinuation group, respectively (p<0.001). Multivariate analysis showed that anti-TNF discontinuation (HR=3.01; 95% CI=1.22-7.43) and ileal CD location (HR=2.36; 95% CI=1.02-5.47) were predictive factors for relapse while inflammatory CD phenotype was a protective factor (HR=0.32; 95% CI=0.11-0.90). Reintroduction of anti-TNF upon relapse was effective and safe.

Anti-TNF discontinuation led to significantly higher relapse rates compared to IMM discontinuation in UC and CD patients on combination therapy. Anti-TNF discontinuation and ileal CD location were identified as predictive factors for relapse while inflammatory CD phenotype was a protective factor. Retreatment after anti-TNF discontinuation was effective and safe.

Spondyloarthritis (SpA) is the most frequent extraintestinal manifestation in patients with inflammatory bowel diseases (IBD). When IBD and spondyloarthritis coexist, musculoskeletal and intestinal disease features should be considered when planning a therapeutic strategy. Treatment options for IBD and SpA have expanded enormously over the last few years, but randomized controlled trials with specific endpoints focused on SpA are not available in the IBD setting. To address this important clinical topic, the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD) and the Italian Society of Rheumatology (SIR) jointly planned to draw updated therapeutic recommendations for IBD-associated SpA using a pseudo-Delphi method. This document presents the official recommendations of IG-IBD and SIR on the management of IBD-associated SpA in the form of 34 statements and 4 therapeutic algorithms. It is intended to be a reference guide for gastroenterologists and rheumatologists dealing with IBD-associated SpA.

The treatment of inflammatory bowel disease has undergone a significant transformation following the introduction of biologic drugs. Thanks to these drugs, treatment goals have evolved from clinical response and remission to more ambitious objectives, such as endoscopic or radiologic remission. However, even though biologics are highly effective, a significant percentage of patients will not achieve an initial response or may lose it over time. We know that there is a direct relationship between the trough concentrations of the biologic and its therapeutic efficacy, with more demanding therapeutic goals requiring higher drug levels, and inadequate exposure being common. Therapeutic drug monitoring of biologic medications, along with pharmacokinetic models, provides us with the possibility of offering a personalized approach to treatment for patients with IBD. Over the past few years, relevant information has accumulated regarding its utility during or after induction, as well as in the maintenance of biologic treatment, in reactive or proactive strategies, and prior to withdrawal or treatment de-escalation. The aim of this document is to establish recommendations regarding the utility of therapeutic drug monitoring of biologics in patients with inflammatory bowel disease, in different clinical practice scenarios, and to identify areas where its utility is evident, promising, or controversial.

The timely introduction and adjustment of the appropriate drug in accordance with previously well-defined treatment goals is the foundation of the approach in the treatment of inflammatory bowel disease (IBD). The therapeutic approach is still evolving in terms of the mechanism of action but also in terms of the possibility of maintaining remission. In patients with achieved long-term remission, the question of de-escalation or discontinuation of therapy arises, considering the possible side effects and economic burden of long-term therapy. For each of the drugs used in IBD (5-aminosalycaltes, immunomodulators, biological drugs, small molecules) there is a risk of relapse. Furthermore, studies show that more than 50% of patients who discontinue therapy will relapse. Based on the findings of large studies and meta-analysis, relapse of disease can be expected in about half of the patients after therapy withdrawal, in case of monotherapy with aminosalicylates, immunomodulators or biological therapy. However, longer relapse-free periods are recorded with withdrawal of medication in patients who had previously been on combination therapies immunomodulators and anti-tumor necrosis factor. It needs to be stressed that randomised clinical trials regarding withdrawal from medications are still lacking. Before making a decision on discontinuation of therapy, it is important to distinguish potential candidates and predictive factors for the possibility of disease relapse. Fecal calprotectin level has currently been identified as the strongest predictive factor for relapse. Several other predictive factors have also been identified, such as: High Crohn's disease activity index or Harvey Bradshaw index, younger age (< 40 years), longer disease duration (> 40 years), smoking, young age of disease onset, steroid use 6-12 months before cessation. An important factor in the decision to withdraw medication is the success of re-treatment with the same or other drugs. The decision to discontinue therapy must be based on individual approach, taking into account the severity, extension, and duration of the disease, the possibility of side adverse effects, the risk of relapse, and patient's preferences.

Background: Metabolite profiling of blood by nuclear magnetic resonance (NMR) is invaluable to clinical biomarker discovery. To ensure robustness, biomarkers require validation in large cohorts and across multiple centres. However, collection procedures are known to impact on the stability of biofluids that may, in turn, degrade biomarker signals. We trialled three blood collection tubes with the aim of solving technical challenges due to preanalytical variation in blood metabolite levels that are common in cohort studies. Methods: We first investigated global NMR-based metabolite variability between biobanks, including the large-scale UK Biobank and TwinsUK biobank of the general UK population, and more targeted biobanks derived from multicentre clinical trials relating to inflammatory bowel disease. We then compared the blood metabolome of 12 healthy adult volunteers when collected into either sodium fluoride/potassium oxalate, lithium heparin, or serum blood tubes using different pre-processing parameters. Results: Preanalytical variation in the method of blood collection strongly influences metabolite composition within and between biobanks. This variability can largely be attributed to glucose and lactate. In the healthy control cohort, the fluoride oxalate collection tube prevented fluctuation in glucose and lactate levels for 24 hours at either 4 °C or room temperature (20 °C). Conclusions: Blood collection into a fluoride oxalate collection tube appears to preserve the blood metabolome with delayed processing up to 24 hours at 4 °C. This method may be considered as an alternative when rapid processing is not feasible.

Maintenance treatment for ulcerative colitis may be discontinued for multiple reasons. This post hoc analysis assessed the efficacy and safety of re-treatment with filgotinib, an oral, once-daily, Janus kinase 1 preferential inhibitor, in the phase 2b/3 SELECTION trial and its long-term extension [LTE] study in ulcerative colitis.

Partial Mayo Clinic Score [pMCS] response and remission were evaluated in patients who received induction with filgotinib 200 mg [FIL200] or 100 mg [FIL100], were randomized to treatment withdrawal [placebo] during maintenance, and following disease worsening, were re-treated with open-label FIL200 in the LTE study. Factors were evaluated for association with pMCS remission at LTE week 12, and safety outcomes were reported.

Analyses included 86 patients [FIL200: n = 51; FIL100: n = 35]. Median time to disease worsening following treatment withdrawal was 15.1 weeks (95% confidence interval [CI]: 9.1-18.7) for FIL200-induced patients and 9.6 weeks [95% CI: 6.3-12.0] for FIL100-induced patients. Three-quarters [75%] of patients achieved a pMCS response within 4-5 weeks of re-treatment in both groups. At LTE week 48, pMCS remission was achieved by 45.1% and 51.4% of FIL200- and FIL100-induced patients, respectively. Factors independently associated with restoring efficacy included no concomitant use of corticosteroids at induction baseline, and high albumin levels, pMCS remission, and endoscopic score at maintenance baseline. No new safety signals were reported among re-treated patients.

In induction responders, re-treatment with FIL200 following temporary withdrawal from therapy restores response and/or remission in the majority of patients within 12 weeks. Re-treatment is well-tolerated. ClinicalTrials.gov identifiers: NCT02914522, NCT02914535.

Endoscopy is an essential tool supporting inflammatory bowel disease diagnosis, and ileocolonoscopy is essential to the diagnostic process because it allows for histological sampling. A decent description of endoscopic lesions may lead to a correct final diagnosis up to 89% of the time. Moreover, endoscopy is key to evaluating endoscopic severity, which in both Crohn's disease and ulcerative colitis is associated with worse disease outcomes (e.g., more frequent advanced therapy requirements or more frequent hospitalizations and surgeries). Endoscopic severity should be reported according to validated endoscopic scores, such as the Mayo endoscopic subscore (MES) or the ulcerative colitis endoscopic index of severity (UCEIS) for ulcerative colitis, the Rutgeerts score for postoperative Crohn's recurrence, and the Crohn's disease endoscopic index of severity (CDEIS) or the simplified endoscopic score for Crohn's disease (SES-CD) for luminal Crohn's disease activity. The measuring of endoscopic activity has become a regulatory agency requirement to increase the objective evaluation of disease activity and drug response. In recent years, the central reviewing of endoscopic videos has become a standard for clinical trials. However, the adjudication paradigm and the type of endoscopic reading may substantially affect trial outcomes, and the reproducibility of all endoscopic scores is not perfect as they require the interpretation of intrinsically subjective images. This paper reviews and discusses the available evidence on inflammatory bowel disease endoscopy.

In Crohn's disease, the treat-to-target strategy has been greatly encouraged and has become a standard of care. In this context, defining the target [remission] constitutes a major stake and is fuelling the literature. Currently, clinical remission [symptom control] is no longer the only objective of treatments since it does not allow to closely control inflammation-induced tissue damage. The introduction of endoscopic remission as a therapeutic target clearly represented progress but this examination remains invasive, costly, not well accepted by patients and does not allow tight control of disease activity. More fundamentally, morphological techniques [e.g. endoscopy, histology, ultrasonography] are limited since they do not evaluate the biological activity of the disease but only its consequences. Besides, emerging evidence suggests that biological signs of disease activity could better guide treatment decisions than clinical parameters. In this context, we stress the necessity to define a novel treatment target: biological remission. Based on our previous work, we propose a conceptual definition of biological remission which goes beyond the classical normalization of inflammatory markers [C-reactive protein and faecal calprotectin]: absence of biological signs associated with the risk of short-term relapse and mid-/long-term relapse. The risk of short-term relapse seems essentially to be characterized by a persistent inflammatory state while the risk of mid-/long-term relapse implies a more heterogeneous biology. We discuss the value of our proposal [guiding treatment maintenance, escalation or de-escalation] but also the fact that its clinical implementation would require overcoming major challenges. Finally, future directions are proposed to better define biological remission.

Tofacitinib is associated with sustained steroid-free remission in patients with ulcerative colitis (UC), with the lowest effective dose recommended for maintenance therapy. However, there are limited real-world data to guide decisions on the optimal maintenance regimen. We aimed to evaluate predictors and outcomes of disease activity after tofacitinib dose de-escalation in this population.

Included were adults with moderate-severe UC treated with tofacitinib between June 2012 and January 2022. The primary outcome was evidence of UC disease activity-related events: hospitalization/surgery, corticosteroid initiation, tofacitinib dose increase, or therapy switch.

Among 162 patients, 52% continued 10 mg twice daily while 48% underwent dose de-escalation to 5 mg twice daily. Cumulative incidence rates of UC events at 12 months were similar in patients with and without dose de-escalation (56% vs 58%; P = .81). In univariable Cox regression among patients with dose de-escalation, an induction course with 10 mg twice daily for more than 16 weeks was protective of UC events (hazard ratio [HR], 0.37; 95% CI, 0.16-0.85) while ongoing severe disease (Mayo 3) was associated with UC events (HR, 6.41; 95% 95% CI, 2.23-18.44), which remained significant after adjusting for age, sex, duration of induction course, and corticosteroid use at dose de-escalation (HR, 6.05; 95% CI, 2.00-18.35). Twenty-nine percent of patients with UC events had their dose re-escalated to 10 mg twice daily, with only 63% able to recapture clinical response at 12 months.

In this real-world cohort, we observed a 56% cumulative incidence of UC events at 12 months in patients with tofacitinib dose de-escalation. Observed factors associated with UC events after dose de-escalation included induction course for fewer than 16 weeks and active endoscopic disease 6 months after initiation.

Background: Inflammatory Bowel Disease (IBD) impacts millions worldwide, presenting a major challenge to healthcare providers and patients. The advent of biologic therapies has enhanced the prognosis, but many patients exhibit primary or secondary non-response, underscoring the need for rigorous monitoring and therapy optimization to improve outcomes. Objective: This narrative review seeks to understand the role of therapeutic drug monitoring (TDM) in optimizing treatment for IBD patients, especially for those on combination therapies of biologics and immunomodulators. Methods: A comprehensive synthesis of the current literature was undertaken, focusing on the application, benefits, limitations, and future directions of TDM in patients receiving a combination of biologic therapies and immunomodulators. Results: While biological therapies have improved outcomes, rigorous monitoring and therapy optimization are needed. TDM has emerged as a pivotal strategy, enhancing outcomes cost-effectively while reducing adverse events. While most data pertain to monotherapies, TDM's applicability also extends to combination therapy. Conclusion: TDM plays a crucial role in the treatment optimization of IBD patients on combination therapies. Further research is needed to fully understand its potential and limitations in the broader context of IBD management.

there are concerns regarding the risk of relapse after discontinuation of anti-tumor necrosis factor (anti-TNF) therapy in patients with inflammatory bowel disease (IBD). A systematic review and meta-analysis were performed to evaluate the risk of relapse after discontinuation of anti-TNF agent in patients, and the response to retreatment with the same anti-TNF agent.

electronic databases were searched to identify relevant studies. Primary outcomes were the pooled percentage of relapses after the withdrawal of anti-TNF agents. Secondary outcomes were the pooled percentage of the response to retreatment with the same anti-TNF agent after relapse.

thirty-seven studies were included in this meta-analysis. The overall risk of relapse after discontinuation of anti-TNF agent was 43 % for ulcerative colitis (UC) and 43 % for Crohn's disease (CD). In UC, the relapse rate was 37 % at 1-2 year, and 58 % at 3-5 years. In CD, the relapse rate was 38 % at 1-2 year, 53 % at 3-5 years, and 49 % at more than five years. When clinical remission was the only criterion for stopping anti-TNF agent, the relapse rate was 42 % in UC and 45 % in CD, which decreased to 40 % in UC and 36 % in CD when clinical remission and endoscopic healing were required. Retreatment with the same anti-TNF agent induced remission again in 78 % of UC patients and 76 % of CD patients.

our meta-analysis showed that a high proportion of IBD patients will relapse after discontinuation of anti-TNF agent. The response to retreatment with the same anti-TNF agent is generally favorable in patients who relapse.

Biologic treatment withdrawal in inflammatory bowel disease patients with prolonged remission may lead to benefits but also increases the risk of getting a relapse. The risk of relapse after biologic withdrawal according to the Dutch STOP-criteria is still unknown. The aim of this study was to compare the cumulative incidence of relapse in inflammatory bowel disease patients that discontinued biologic therapy after applying the STOP-criteria with patients who maintained biologic therapy. We performed a mono-centre, observational, retrospective study by evaluating relapse risk of patients treated with biologic agents who discontinued this treatment according to the STOP-criteria (STOP-group) compared to patients who were in remission for more than 3 years before withdrawal (LATERSTOP-group) and patients who continued their biologic (MAINTAIN-group). The cumulative risk was calculated at 12 and 36 months using the log-rank test to compare Kaplan-Meier curves. Eighty-three of 398 patients that used biologics between 1 January 2010 and 1 January 2020 were included. The cumulative relapse incidences in the STOP-group and the LATERSTOP-group were, respectively, 29% and 42% at 12 months and 47% versus 58% at 36 months. Patients in the MAINTAIN-group showed a lower (p = 0.03) cumulative relapse incidence of 10% at 12 months and 18% at 36 months. Patients who discontinued their biologic therapy according to the STOP-criteria had significantly more relapses at 12 and 36 months than patients who maintained biologic treatment.

Calprotectin is a heterodimeric calcium- and zinc-binding protein mainly derived from the cytoplasm of neutrophils that has direct antimicrobial functions and a role in the regulation of the innate immune response. It can be found in various biological compartments, in particular, the stool, with concentrations related to the level of mucosal inflammation. The measurement of fecal calprotectin has thus been recognized as a useful surrogate marker to distinguish patients with inflammatory bowel disease from those with irritable bowel syndrome. Moreover, it allows the monitoring of intestinal inflammation with a high negative predictive value, making it possible to exclude the diagnosis of inflammatory bowel disease for symptomatic patients. It also shows high sensitivity for the identification of patients requiring additional examinations for diagnosis, such as colonoscopy, and the evaluation of therapeutic responses, providing evidence of relapse or mucosal healing, which can lead to the intensification or reduction of treatment. As calprotectin levels are a measure of mucosal inflammation, high fecal concentrations are also found in other diseases with an inflammatory component, such as infectious enteritis or colorectal cancer. Interpretation of the concentration must therefore always take into account the clinical history and symptoms specific to each patient.

Effectiveness of limited available therapies for pediatric inflammatory bowel disease has reached stagnation. Previous non-invasive monitoring strategies have relied upon cumbersome tools to evaluate clinical symptoms and biochemical markers that do not reflect endoscopic activity or respond quickly to treatments. Novel, patient-centric, and highly accurate, monitoring strategies with a focus on intestinal ultrasound for a direct, precise monitoring of activity to achieve disease modification are now possible. Ultimately, research on the optimal tight control monitoring strategies, individualized to each pediatric inflammatory bowel disease patient, are in development and offer a hope to potential therapeutic ceiling breakthrough on the horizon.

Crohn's disease (CD) is characterized by the development of complications over the course of the disease. It is crucial to identify predictive factors of disabling disease, in order to target patients for early intervention. We evaluated risk factors of disabling CD and developed a prognostic model.

In total, 511 CD patients were retrospectively analyzed. Univariate and multivariate logistic regression analyses were used to identify demographic, clinical, and biological risk factors. A predictive nomogram model was developed in a subgroup of patients with noncomplicated CD (inflammatory pattern and no perianal disease).

The rate of disabling CD within 5 years after diagnosis was 74.6%. Disabling disease was associated with gender, location of disease, requirement of steroids for the first flare, and perianal lesions. In the subgroup of patients (310) with noncomplicated CD, the rate of disabling CD was 80%. In the multivariate analysis age at onset <40 years (OR = 3.46, 95% confidence interval [CI] = 1.52-7.90), extensive disease (L3/L4) (OR = 2.67, 95% CI = 1.18-6.06), smoking habit (OR = 2.09, 95% CI = 1.03-4.27), requirement of steroids at the first flare (OR = 2.20, 95% CI = 1.09-4.45), and albumin (OR = 0.59, 95% CI = 0.36-0.96) were associated with development of disabling disease. The developed predictive nomogram based on these factors presented good discrimination, with an area under the receiver operating characteristic curve of 0.723 (95% CI: 0.670-0.830).

We identified predictive factors of disabling CD and developed an easy-to-use prognostic model that may be used in clinical practice to help identify patients at high risk and address treatment effectively.

Inflammatory bowel disease (IBD) comprises a group of chronic conditions characterized by relapsing and remitting inflammation of the gastrointestinal tract. The incidence is increasing worldwide, and the therapeutic options for management are expanding. Endoscopy is the gold standard investigation for diagnosis of IBD and for assessing mucosal healing, which is increasingly being used as a measure of disease control. However, it is an invasive procedure that is unpleasant for patients and expensive and time-consuming for hospitals. Fecal calprotectin has been shown to be an accurate surrogate marker of gastrointestinal inflammation in IBD.

Fecal calprotectin was initially used for the diagnosis of IBD but is now recognized as having a role in assisting in assessment of disease activity, prediction of relapse, and informing decisions around therapy and may help to minimize requirement for endoscopy. However, there are various preanalytical and analytical factors that can affect interpretation of the results; these need to be understood to optimize clinical care.

Preanalytical and analytical factors that can potentially influence fecal calprotectin concentrations are examined, and an overview is provided of clinical situations in which fecal calprotectin is commonly measured.

The cost of caring for patients with inflammatory bowel disease (IBD) continues to increase worldwide. The cause is not only a steady increase in the prevalence of Crohn's disease and ulcerative colitis in both developed and newly industrialised countries, but also the chronic nature of the diseases, the need for long-term, often expensive treatments, the use of more intensive disease monitoring strategies, and the effect of the diseases on economic productivity. This Commission draws together a wide range of expertise to discuss the current costs of IBD care, the drivers of increasing costs, and how to deliver affordable care for IBD in the future. The key conclusions are that (1) increases in health-care costs must be evaluated against improved disease management and reductions in indirect costs, and (2) that overarching systems for data interoperability, registries, and big data approaches must be established for continuous assessment of effectiveness, costs, and the cost-effectiveness of care. International collaborations should be sought out to evaluate novel models of care (eg, value-based health care, including integrated health care, and participatory health-care models), as well as to improve the education and training of clinicians, patients, and policy makers.

The long-term management of patients with inflammatory bowel disease (IBD) is still a matter of debate, and no clear guidelines have been issued. In clinical practice, gastroenterologists often have to deal with patients in prolonged remission after immunomodulatory or immunosuppressive therapies. When planning an exit strategy for drug withdrawal, the risk of disease relapse must be balanced against the risk of drug-related adverse events and healthcare costs. Furthermore, there is still a dearth of data on the withdrawal of novel biologics, such as the anti-α4β7 integrin antibody (vedolizumab) and anti-IL12/23 antibody (ustekinumab), as well as the small molecule tofacitinib. Models for estimating the risk of disease relapse and the efficacy of retreatment should be evaluated according to the patient's age and IBD phenotype. These models should guide clinicians in programming a temporary drug withdrawal after discussing realistic outcomes with the patient. This would shift the paradigm from an exit strategy to a holiday strategy.

A cure for Crohn's disease (CD), a chronic inflammatory disease of the gastrointestinal tract of unknown etiology, is not available, so patients require lifelong management to keep inflammation under control. The therapeutic armamentarium has expanded with approval of several biological drugs, including infliximab, adalimumab, vedolizumab and ustekinumab - monoclonal antibodies that target different inflammatory pathways - and darvadstrocel, a suspension of expanded human allogeneic, adipose-derived, mesenchymal stromal cells for the treatment of refractory complex perianal fistula. Notwithstanding existing practice guidelines on medical therapy for CD, the Italian Group for the Study of Inflammatory Bowel Disease felt the need to issue new guidelines focused on the use of biologics for managing the intestinal manifestations of CD and based on the GRADE methodology. This document presents recommendations regarding six clinical settings, from the induction to the maintenance of clinical remission, and from optimization and de-escalation of treatments to dealing with perianal CD and post-operative recurrence. The 19 evidence-based statements are supported by information on the quality of the evidence, agreement rate among panel members, and panel comments mainly based on evidence from real world studies.

Inflammatory bowel disease is a chronic disease of unknown origin that requires long-term treatment. The optical duration of maintenance treatment once remission has been achieved remains unclear. When discussing a de-escalation strategy, not only the likelihood of relapse but also, the outcome of retreatment for relapse after de-escalation should be considered. Previous evidence has demonstrated controversial results for risk factors for relapse after de-escalation due to the various definitions of remission and relapse. In fact, endoscopic or histologic remission has been suggested as a treatment target; however, it might not always be indicative of a successful drug withdrawal. For better risk stratification of relapse after de-escalation, it may be necessary to evaluate both the current and previous treatments. Following de-escalation, biomarkers should be closely monitored. In addition to the risk of relapse, a comprehensive understanding of the overall outcome, such as the long-term safety, patient quality of life, and impact on healthcare costs, is necessary. Therefore, a shared decision-making with patients on a case-by-case basis is imperative.

The combination of infliximab and immunosuppressant therapy is a standard management strategy for patients with Crohn's disease. Concerns regarding the implications of long-term combination therapy provided the rationale for a formal clinical trial of treatment de-escalation. Our aim was to compare the relapse rate and the time spent in remission over 2 years between patients continuing combination therapy and those stopping infliximab or immunosuppressant therapy.

This multicentre, open-label, randomised controlled trial was performed in 64 hospitals in seven countries in Europe and Australia. Adult patients with Crohn's disease in steroid-free clinical remission for more than 6 months, on combination therapy of infliximab and immunosuppressant therapy for at least 8 months were randomly assigned (1:1:1) to either continue combination therapy (combination group), discontinue infliximab (infliximab withdrawal group), or discontinue immunosuppressant therapy (immunosuppressant withdrawal group). Randomisation was stratified according to disease duration before start of first anti-TNF treatment (≤2 or >2 years), failure of immunosuppressant therapy before start of infliximab, and presence of ulcers at baseline endoscopy. The patient number and group of each stratum were assigned by a central online randomisation website. Treatment was optimised or resumed in case of relapse in all groups. Participants, those assessing outcomes, and those analysing the data were not masked to group assignment. The coprimary endpoints were the relapse rate (superiority analysis) and time in remission over 2 years (non-inferiority analysis, non-inferiority margin 35 days). Analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT02177071, and with EU Clinical Trials Register, EUDRACT 2014-002311-41. The trial was completed in April, 2021.

Between Nov 2, 2015, and April 24, 2019, 254 patients were screened. Of these, 211 were randomised and 207 were included in the final analysis (n=67 in the combination group, n=71 in the infliximab withdrawal group, and n=69 in the immunosuppressant withdrawal group). 39 patients had a relapse (eight [12%] of 67 in the combination group, 25 [35%] of 71 in the infliximab withdrawal group, six [9%] of 69 in the immunosuppressant withdrawal group). 2-year relapse rates were 14% (95% CI 4-23) in the combination group, 36% (24-47) in the infliximab withdrawal group, and 10% (2-18) in the immunosuppressant withdrawal group (hazard ratio [HR] 3·45 [95% CI 1·56-7·69], p=0·003, for infliximab withdrawal vs combination, and 4·76 [1·92-11·11], p=0·0004, for infliximab withdrawal vs immunosuppressant withdrawal). Of 28 patients who had a relapse and were retreated or optimised according to protocol, remission was achieved in 25 patients (one of two in the combination group, 22 of 23 in the infliximab withdrawal group, and two of three in the immunosuppressant withdrawal group). The mean time spent in remission over 2 years was 698 days (95% CI 668-727) in the combination group, 684 days (651-717) in the infliximab withdrawal group, and 706 days (682-730) in the immunosuppressant withdrawal group. The difference in restricted mean survival time in remission was -14 days (95% CI -56 to 27) between the infliximab withdrawal group and the combination group and -22 days (-62 to 16) between the infliximab withdrawal group and the immunosuppressant withdrawal group. The 95% CIs contained the non-inferiority threshold (-35 days). We recorded 31 serious adverse events, in 20 patients, with no difference in frequency between groups. The most frequent serious adverse events were infections (four in the combination group, two in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group) and Crohn's disease exacerbation (three in the combination group, four in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group). No death nor malignancy was recorded.

In patients with Crohn's disease in sustained steroid-free remission under combination therapy with infliximab and immunosuppressant therapy, withdrawal of infliximab should only be considered after careful assessment of risks and benefits for each patient, whereas withdrawal of immunosuppressant therapy could generally represent a preferable strategy when considering treatment de-escalation.

European Union's Horizon 2020.