Long-term outcome of risankizumab in Crohn's disease: a real-world GETAID study.

INTRODUCTION: The aim of this study was to assess the long-term effectiveness and safety of risankizumab maintenance treatment in a large real-world cohort of patients with CD. PATIENTS AND METHODS: From May 2021 to August 2023, all consecutive CD patients treated with risankizumab in 25 GETAID centers have been retrospectively included. The primary endpoint was steroid-free clinical remission (Harvey Bradshaw Index (HBI) <5) at 52 weeks. RESULTS: Of the 174 patients included, 99%, 93%, and 96% had been previously exposed to anti-TNF, vedolizumab, and ustekinumab, respectively. All patients had received ≥3 biologics and 108 (62%) had previous intestinal resection. Median follow-up was 13.7 (10.0-18.1) months. The rates of steroid-free clinical remission and clinical remission at week 26 were 47% (72/152) and 52% (79/152), and 46% (58/125), and 48% (60/125) at week 52, respectively. Risankizumab persistence rates were 94%, 89%, and 79% at weeks 12, 26, and 52, respectively. At the end of follow-up, 45 (45/174, 26%) patients had discontinued risankizumab (loss of response, 42%; primary failure, 37%; intolerance, 13%). Thirty-six patients (36/174, 20.9%) were hospitalized and 22 (22/174, 12.6%) required intestinal resection. Fifty-one (29%) patients had an adverse event including 26 (15%) serious adverse events (CD flare, n=17). One death (myocardial infarction) and one cancer (papillary thyroid carcinoma) were observed. CONCLUSION: This is the first real-life study to report long-term outcomes in patients with refractory CD treated with risankizumab. Half of the patients achieved steroid-free clinical remission after one year, and the safety profile was consistent with the literature.

Long-term risk of delayed postoperative Crohn's disease recurrence in patients with no or mild endoscopic recurrence at first assessment.

BACKGROUND: Early endoscopic evaluation is recommended for assessment of postoperative recurrence (POR) of Crohn's disease (CD) but no further monitoring recommendations are available. AIM: To evaluate the long-term outcome of patients without endoscopic POR at first endoscopic assessment. METHODS: Retrospective four-centre study including consecutive CD patients with ileocolonic resection (ICR) without endoscopic POR (Rutgeerts score i0-i1) at first endoscopic assessment performed within 18 months from ICR. All patients had a clinical follow-up ≥24 months and at least one further endoscopic assessment. Main outcomes were endoscopic, clinical and surgical POR, need for rescue therapy and "delayed POR" (any need for rescue therapy or clinical or surgical POR) during follow-up. RESULTS: Overall, 183 patients were included (79% with risk factors for POR, 44% without postoperative prophylaxis). Endoscopic POR was observed in 42% of patients. Clinical POR-free survival was 89.4% and 81.5% at 3 and 5 years, and delayed POR-free survival was 76.9% and 63.4% at 5 and 10 years, respectively. In multivariate analysis, postoperative prophylaxis (HR .55; 95% CI .325-.942) and active smoking (HR 1.72; 95%CI 1.003-2.962) were independent risk factors for clinical POR, whereas presence of mild endoscopic lesions at index ileocolonoscopy (i1) was the only risk factor for delayed POR (HR 1.824; 95% CI 1.108-3.002). CONCLUSIONS: Long-term risk of POR among patients with no or mild endoscopic lesions at first ileocolonoscopy after surgery is steadily low, being higher among smokers, in the absence of postoperative prophylaxis and when mild endoscopic lesions are observed in the first endoscopic assessment.

Simulated cost-effectiveness of a novel precision-guided dosing strategy in adult patients with Crohn's disease initiating infliximab maintenance therapy.

BACKGROUND: Patients with Crohn's disease (CD) who lose response to biologics experience reduced quality of life (QoL) and costly hospitalizations. Precision-guided dosing (PGD) provides a comprehensive pharmacokinetic (PK) profile that allows for biologic dosing to be personalized. We analyzed the cost-effectiveness of infliximab (IFX) PGD relative to two other dose intensification strategies (DIS). METHODS: We developed a hybrid (Markov and decision tree) model of patients with CD who had a clinical response to IFX induction. The analysis had a US payer perspective, a base case time horizon of 5 years, and a 4-week cycle length. There were three IFX dosing comparators: PGD; dose intensification based on symptoms, inflammatory markers, and trough IFX concentration (DIS1); and dose intensification based on symptoms alone (DIS2). Patients that failed IFX initiated ustekinumab, followed by vedolizumab, and conventional therapy. Transition probabilities for IFX were estimated from real-world clinical PK data and interventional clinical trial patient-level data. All other transition probabilities were derived from published randomized clinical trials and cost-effectiveness analyses. Utility values were sourced from previous health technology assessments. Direct costs included biologic acquisition and infusion, surgeries and procedures, conventional therapy, and lab testing. The primary outcomes were incremental cost-effectiveness ratios (ICERs). The robustness of results was assessed via one-way sensitivity, scenario, and probabilistic sensitivity analyses (PSA). RESULTS: PGD was the cost-effective IFX dosing strategy with an ICER of 122,932 $ per quality-adjusted life year (QALY) relative to DIS1 and dominating DIS2. PGD had the lowest percentage (1.1%) of patients requiring a new biologic through 5 years (8.9% and 74.4% for DIS1 and DIS2, respectively). One-way sensitivity analysis demonstrated that the cost-effectiveness of PGD was most sensitive to the time between IFX doses. PSA demonstrated that joint parameter uncertainty had moderate impact on some results. CONCLUSIONS: PGD provides clinical and QoL benefits by maintaining remission and avoiding IFX failure; it is the most cost-effective under conservative assumptions.

Acute severe ulcerative colitis management: unanswered questions and latest insights.

Acute severe ulcerative colitis (ASUC) is a distinctive ulcerative colitis flare presentation characterised by the presence of systemic inflammation as well as bloody diarrhoea, and occurs at least once in 25% of patients with ulcerative colitis during their disease course. Each episode carries a risk of complications, need for colectomy, and mortality. Little is known about ASUC pathogenesis, although impaired host-microbiota crosstalk involving pathobionts is suspected. In this Review, we discuss unanswered questions and results from the latest research on the medical-first-line, second-line, and potential third-line therapies-and surgical management of ASUC. We detail promising options for management, such as the use of enteral nutrition in combination with intravenous steroids, the ability to predict early failure of first-line or second-line therapies, and the emerging role of JAK inhibitors. An optimal framework to personalise therapy on the basis of multiomics tools is yet to be developed.

Pragmatic trial design to compare real-world effectiveness of different treatments for inflammatory bowel diseases: the PRACTICE-IBD European consensus.

BACKGROUND AND AIMS: Pragmatic studies designed to test interventions in everyday clinical settings can successfully complement the evidence from registration and explanatory clinical trials. The European consensus project PRACTICE-IBD was developed to identify essential criteria and address key methodological issues needed to design valid comparative pragmatic studies in inflammatory bowel diseases (IBDs). METHODS: Statements were issued by a panel of 11 European experts in IBD management and trial methodology on four main topics: (I) study design; (II) eligibility, recruitment and organization, flexibility; (III) outcomes; (IV) analysis. The consensus process followed a modified Delphi approach, involving two rounds of assessment and rating of the level of agreement (1 to 9; cut-off ≥7 for approval) with the statements by 18 additional European experts in IBD. RESULTS: At the first voting round, 25 out of the 26 statements reached a mean score ≥7. Following the discussion that preceded the second round of voting, it was decided to eliminate two statements and to split one into two. At the second voting round, 25 final statements were approved: 7 for study design, 6 for eligibility, recruitment and organization, flexibility, 8 for outcomes, and 4 for analysis. CONCLUSIONS: Pragmatic randomized clinical trials can address important questions in IBD clinical practice, and may provide complementary high-level evidence, as long as they follow a methodologically rigorous approach. These 25 statements intend to offer practical guidance in the design of high-quality pragmatic clinical trials that can aid decision making in choosing a management strategy for IBDs.

Histological healing induced by tofacitinib in ulcerative colitis: A multicentre study.

BACKGROUND: While the efficacy of tofacitinib to induce and maintain clinical and endoscopic remission is well established in ulcerative colitis (UC), little is known about its efficacy to induce histological remission. METHODS: We conducted a retrospective multicentric cohort study. UC patients ≥ 16 years treated by tofacitinib in whom histological activity has been evaluated before and after induction were eligible. The primary endpoint was the histological remission at the end of induction, assessed by the Nancy index and the epithelial neutrophilic infiltrate. RESULTS: A total of 42 patients with UC (93% previously exposed to an anti-TNF and 81% to vedolizumab) were included between July 2018 and April 2022 and were followed for a median duration of 84 weeks [IQR, 35-134]. At the end of induction period (whether prolonged or not), 19% and 24% of patients achieved histological remission, using the Nancy index and the epithelial neutrophilic infiltrate, respectively. Survival without tofacitinib discontinuation was significantly longer in patients without epithelial neutrophilic infiltrate at the end of induction (whether prolonged or not) compared with patients with epithelial neutrophilic infiltrate (p = 0.036). CONCLUSION: Tofacitinib induced histological remission in one fifth to one quarter of patients with UC who have previously failed anti-TNF or/and vedolizumab after induction (whether prolonged or not).

Lymphoma In Patients With Inflammatory Bowel Disease: A Multicenter Collaborative Study Between Getaid And Lysa.

BACKGROUND: IBD is associated with an increased risk of developing lymphoma. Although recent data clarifies lymphoma epidemiology in IBD patients, clinical and pathological characteristics of lymphoma occurring in IBD remain ill-known. METHODS: Patients with IBD and lymphoma were retrospectively identified in the framework of a national collaborative study including the Groupe d'Étude Thérapeutique des Affections Inflammatoires du Tube Digestif (GETAID) and the Lymphoma Study Association (LYSA). We characterized clinical and prognostic features for the 3 most frequent lymphoma subtypes occurring in IBD. We performed a multicentric case-control study. Controls (lymphoma de novo) were matched (5:1) to cases on gender, age at diagnosis, lymphoma subtype, year of diagnosis, IPI/FLIPI indexes. Overall survival (OS) and progression free survival were compared between cases and controls. RESULTS: 133 IBD patients with lymphoma were included (males = 62.4 %, median age at lymphoma diagnosis = 49 years in males ; 42 in females). Most had Crohn's disease (73.7 %) and were exposed to thiopurines (59.4 %). The most frequent lymphoma subtypes were diffuse large B cell lymphoma (DLBCL, 45.1 %), Hodgkin lymphoma (HL, 18.8 %), and follicular lymphoma (FL, 10.5 %). When matched with 365 controls, prognosis was improved in IBD patients with DLBCL compared to controls (p = 0.0064, hazard ratio = 0.36) or similar (HL and FL). CONCLUSION: Lymphomas occurring in IBD patients do not seem to have a worse outcome than in patients without IBD. Due to the scarcity of this situation, those patients should be managed in expert centers.

The risk of COVID-19 in IBD patients is increased by urban living and is not influenced by disease activity or intravenous biologics.

Background: Patients with inflammatory bowel disease (IBD) may have a modified immune response to SARS-CoV-2. The objectives were to evaluate the prevalence of COVID-19 in patients treated with infliximab or vedolizumab, to analyze the factors associated with the infection, the impact of treatments and trough levels. Methods: Patients with IBD treated with intravenous biologics in 14 French centers were included between March and June 2020 and followed-up for 6 months. Blood samples were collected for serologies and trough levels. The analysis of factors associated with COVID-19 was conducted in a matched 1:1 case-control sub-study with positive patients. Results: In total, 1026 patients were included (74.9% infliximab). Over the follow-up period, 420 patients reported the occurrence of COVID-19 symptoms; 342 had been tested of whom 18 were positive. At the end of follow-up, 38 patients had a positive serology. Considering both nasal tests and serologies together, 46 patients (4.5%) had been infected. The risk of COVID-19 was related neither to the use of treatments (whatever the trough levels) nor to disease activity. Infections were more frequent when using public transport or living in flats in urban areas. Conclusions: The prevalence rate of COVID-19 in this IBD population treated with intravenous infliximab or vedolizumab was the same as the one in the French population before the start of the vaccination campaign. The risk was increased by urban living and was not influenced by disease activity or biologics. Sanitary barrier measures remain the best way to protect against SARS-CoV-2 in patients with IBD in biological therapy.

Prevalence of and Factors Associated With Extraintestinal Manifestations and Their Remission in Inflammatory Bowel Disease: The EXTRA-Intestinal Manifestation Prospective Study From the Groupe d'Etude Thérapeutique des Affections Inflammatoires du Tube Digestif.

INTRODUCTION: Extraintestinal manifestations (EIMs) of inflammatory bowel disease (IBD) are challenging clinical situation. No prospective study assessed remission risk factors of EIMs. The aim of this study was to prospectively investigate the epidemiology, risk factors of EIM occurrence, and EIM remission in a large IBD cohort. METHODS: We conducted a cross-sectional study in 30 French referral centers. Between May 2021 and June 2021, all consecutive patients attending to hospital appointment were systematically invited to fill out a questionnaire. RESULTS: A total of 1,971 consecutive patients with IBD were analyzed. There were 1,056 women (53.8%), and the median age of patients was 41 years (31-54). The median disease duration was 11 years (1-18). Overall, 544 (27.6%) had at least 1 EIM. In 20.2% of cases, patients had multiple EIMs. The most frequent EIMs were rheumatological (19%) and dermatological (10%) manifestations. Immunosuppressant treatment (odds ratio [OR] = 2.56; P < 0.001) was a risk factor of EIM, while the Montreal A3 classification (OR = 0.61, P = 0.023) and male gender (OR = 0.61, P < 0.001) were associated with a lower risk of EIM occurrence. IBD current clinical remission (OR = 2.42; P < 0.001) and smoking cessation (OR = 2.98; P < 0.001) were associated factors of EIM remission. Conversely, age at IBD diagnosis (OR = 0.98; P < 0.018) was associated with a lower risk of EIM remission. DISCUSSION: One quarter of patients had at least 1 EIM. Beyond factors associated with the presence of EIMs, patients with IBD current clinical remission and smoking cessation are more likely to achieve EIM remission, while increasing age at IBD diagnosis is associated with decreased chance of remission.

Review article: Updated management of acute severe ulcerative colitis: From steroids to novel medical strategies.

Acute severe ulcerative colitis (ASUC) occurs in up to 25% of patients with ulcerative colitis (UC). Therapeutic approaches have evolved during the past years with the increasing bio exposure of admitted patients and the extension of the number of approved drugs for UC. In this review, we aimed to summarize the latest evidence in short-term and long-term medical strategies for ASUC. In addition to general principles such as venous thromboembolism prophylaxis, screening for triggering and worsening factors and close monitoring, first-line therapy for ASUC remains intravenous corticosteroids. In naive patients, the optimum maintenance strategy for steroid-responding patients does not necessarily include biologics. Second-line therapy includes infliximab or calcineurin inhibitors (CNIs) with similar short- and long-term colectomy rates. Despite its pathophysiological relevance, there is insufficient evidence to promote intensified induction with infliximab. Prior treatment exposure is a cornerstone for guiding therapeutic choice of short- and long-term therapies in the context of ASUC: in anti-TNF exposed patients, CNIs may be favored as a bridge therapy to vedolizumab or ustekinumab. Third-line salvage therapy could be a therapeutic option in selected patients referred to expert centers. Additionally, evidence is accumulating regarding the use of tofacitinib in ASUC.

Obesity in adult patients with inflammatory bowel disease: Clinical features and impact on disability. A cross-sectional survey from the GETAID.

BACKGROUND: In recent years, an increasing prevalence of obesity in inflammatory bowel disease (IBD) has been observed. However, only a few studies have focused on the impact of overweight and obesity on IBD-related disability. AIMS: To identify the factors associated with obese and overweight patients with IBD, including IBD-related disability. PATIENTS AND METHODS: In this cross-sectional study, we included 1704 consecutive patients with IBD in 42 centres affiliated with the Groupe d'Etude Therapeutique des Affections Inflammatoires du tube Digestif (GETAID) using a 4-page questionnaire. Factors associated with obesity and overweight were assessed using univariate and multivariate analyses (odds ratios (ORs) are provided with 95% confidence intervals). RESULTS: The prevalence rates of overweight and obesity were 24.1% and 12.2%, respectively. Multivariable analyses were stratified by age, sex, type of IBD, clinical remission and age at diagnosis of IBD. Overweight was significantly associated with male sex (OR = 0.52, 95% CI [0.39-0.68], p < 0.001), age (OR = 1.02, 95% CI [1.01-1.03], p < 0.001) and body image subscore (OR = 1.15, 95% CI [1.10-1.20], p < 0.001) (Table 2). Obesity was significantly associated with age (OR = 1.03, 95% CI [1.02-1.04], p < 0.001), joint pain subscore (OR = 1.08, 95% CI [1.02-1.14], p < 0.001) and body image subscore (OR = 1.25, 95% CI [1.19-1.32], p < 0.001) (Table 3). CONCLUSION: The increasing prevalence of overweight and obesity in patients with IBD is associated with age and poorer body image. A holistic approach to IBD patient care should be encouraged to improve IBD-related disability and to prevent rheumatological and cardiovascular complications.

Time trend in surgical indications and outcomes in ulcerative colitis-A two decades in-depth retrospective analysis.

BACKGROUND: Recent data regarding the impact of biologics and new surgical techniques on the indications and outcomes of colectomy for ulcerative colitis (UC) are limited. AIMS: The present study aimed at determining the trend of colectomy in UC by comparing colectomy indications and outcomes between 2000 and 2010 and 2011-2020. METHODS: This observational retrospective study was conducted in two tertiary hospitals, including consecutive patients who underwent colectomy between 2000 and 2020. All data concerning UC history, treatment and surgeries were collected. RESULTS: Among the 286 patients included, 87 underwent colectomy in 2001-2010 and 199 in 2011-2020. Patients' characteristics were similar between groups, except for prior biologic exposure (50.6 % vs. 74.9%; p<0.001). The indications of colectomy significantly decreased for refractory UC (50.6 % vs. 37.7%; p = 0.042), but were similar for acute severe UC (36.8 % vs. 42.2%; p = 0.390) and (pre)neoplastic lesions (12.6 % vs. 20.1%; p = 0.130). A widespread use of laparoscopy (47.7 % vs. 81.4%; p<0.001) was associated with fewer early complications (12.6 % vs. 5.5%; p = 0.038). CONCLUSION: Over the last two decades, the proportion of surgery for refractory UC significantly decreased compared to other surgical indications while surgical outcomes improved despite larger exposure to biologics.

Preoperative Predictors of Neoplasia in Patients Undergoing Small Bowel Resection for Complicated Crohn's Disease: A Multicentre Case-Control Study.

Crohn's disease (CD) is associated with an increased risk of small bowel neoplasia (SBN). We aimed to assess preoperative predictors of SBN in CD patients. We conducted a retrospective case-control study including CD patients who underwent surgery: cases were diagnosed with SBN on histopathological analysis and controls had no neoplasia. Preoperative cross-sectional imaging was reviewed by a panel of blinded expert radiologists. Fifty cases were matched to one hundred and fifty consecutive controls. In multivariable analysis, predictors of SBN were age ≥ 50 years (OR = 28, 95% CI = 5.05-206), median CD duration ≥ 17.5 years (OR = 4.25, 95% CI = 1.33-14.3), and surgery for stricture (OR = 5.84, 95% CI = 1.27-35.4). The predictors of small bowel adenocarcinoma were age ≥ 50 years (OR = 5.14, 95% CI = 2.12-12.7), CD duration ≥ 15 years (OR = 5.65, 95% CI = 2.33-14.3), and digestive wall thickening > 8 mm (OR = 3.79, 95% CI = 1.45-11.3). A predictive score based on the aforementioned factors was constructed. Almost 73.7% of patients with a high score had SBA. Old age, long small bowel CD duration, and stricture predicted the presence of SBN, particularly adenocarcinoma when patients have digestive wall thickening > 8 mm on preoperative imaging.

Prevalence and Determinants of Fatigue in Patients with IBD: A Cross-Sectional Survey from the GETAID.

BACKGROUND: Fatigue is commonly reported by patients with inflammatory bowel disease [IBD], but the determinants of IBD-related fatigue have yet to be determined. AIMS: To identify the factors associated with fatigue in a large population of patients with IBD. PATIENTS AND METHODS: Fatigue and nine other IBD-related disability dimensions were assessed in a cohort of 1704 consecutive patients with IBD using the IBD-disk questionnaire in a cross-sectional survey of 42 French and Belgian centres. Fatigue and severe fatigue were defined as energy subscores >5 and >7, respectively. Determinants of fatigue were assessed using univariate and multivariate analyses (odds ratios [ORs] are provided with 95% confidence intervals). RESULTS: The prevalence rates of fatigue and severe fatigue were 54.1% and 37.1%, respectively. Both fatigue and severe fatigue were significantly higher in patients with active disease than in patients with inactive disease [64.9% vs 44.7% and 47.4% vs 28.6%, respectively; p < 0.001 for both comparisons]. In the multivariate analysis stratified by age, sex, type of IBD and IBD activity, fatigue was associated with age >40 years (OR = 0.71 [0.54-0.93]), female sex (OR = 1.48 [1.13-1.93]) and IBD-related sick leave (OR = 1.61 [1.19-2.16]), and joint pain (OR = 1.60 [1.17-2.18]), abdominal pain (OR = 1.78 [1.29-2.45]), regulating defecation (OR = 1.67 [1.20-2.32]), education and work (OR = 1.96 [1.40-2.75]), body image (OR = 1.38 [1.02-1.86]), sleep (OR = 3.60 [2.66-4.88]) and emotions (OR = 3.60 [2.66-4.88]) subscores >5. CONCLUSION: Determinants of fatigue are not restricted to IBD-related factors but also include social factors, sleep and emotional disturbances, thus supporting a holistic approach to IBD patient care.

Management of Inflammatory Bowel Disease in Patients with Current or Past Malignancy.

Immunomodulators, conventional immunosuppressants, and/or biologics are used more often, earlier, and longer than before in patients with inflammatory bowel disease (IBD). Along with this, the lifetime risk for cancer is estimated to be 33% in the general population in Europe. Thus, physicians face therapeutic choices in an increasing number of IBD patients with current or past malignancy. Few data are available so far for managing this IBD subpopulation and this clinical concern still remains a critical situation for four reasons: (i) risk of reactivation of dormant micrometastasis with immunomodulators is of major concern, (ii) there is a knowledge gap about the safety of the most recent molecules, (iii) current guidelines do not recommend the use of immunomodulators within 2-5 years after a diagnosis of cancer, (iv) patients with previous cancers are excluded from clinical trials. There is a lack of scientific evidence supporting the non-use of immunomodulators in IBD patients with previous cancer. Indeed, accumulative data suggest that the risk for recurrent and new cancer in patients with a history of cancer is not increased by thiopurines and anti-TNF agents. Most recently, cohort studies have found no differences in incident cancer rates in IBD patients with prior malignancy treated with vedolizumab or ustekinumab compared to those treated with anti-TNF agents. Therefore, decisions should be shared by the oncologist and the patient, considering the natural history of cancer, the time elapsed since cancer diagnosis, and IBD prognosis.

Should we Target Complete Endoscopic Healing in Patients with Acute Severe Ulcerative Colitis?

BACKGROUND: Achieving endoscopic healing is a recommended target in ulcerative colitis [UC]. However, little is known about desirable goals in patients with acute severe UC [ASUC]. Taking advantage of the long-term follow-up of clinical trial patients with steroid-refractory ASUC, the present analysis aimed to quantify the observed association between the Mayo endoscopic sub-score [MES], 0 or 1, at clinical trial end and patients' long-term disease outcome. METHODS: Patients in the prospective CYSIF clinical trial were included in the present analysis if they had achieved steroid-free clinical remission with an MES of 0 or 1 at the end of the trial, at day 98. Events during long-term follow-up had been retrospectively collected. The primary endpoint for this complementary analysis was the occurrence of an event, death or disease relapse [defined by recurrence of symptoms with need for a new systemic treatment or colectomy]. RESULTS: Forty-four patients were included in the present analysis. When censoring follow-up at 5 years, six and nine events were observed among 26 and 18 patients having an MES of 0 and 1, respectively. Survival without disease relapse at 1, 2 and 5 years was respectively 88 ±â€…6, 81 ±â€…8 and 77 ±â€…8% in patients with MES of 0, and 72 ±â€…11, 53 ±â€…12 and 46 ±â€…12% in those with MES of 1 [hazard ratio: 2.8; 95% confidence interval: 1.0-8.0; p = 0.042]. CONCLUSION: In a cohort of patients admitted for ASUC in whom clinical and endoscopic healing has been achieved with a second-line medical therapy, better survival without disease relapse was observed with complete endoscopic healing.