Difficult-to-treat inflammatory bowel disease: Effectiveness and safety of 4th and 5th lines of treatment.

BACKGROUND: Many patients with inflammatory bowel disease (IBD) have signs or symptoms of active disease despite multiple treatment attempts. This emerging concept is defined as difficult-to-treat IBD. AIM: The objective of this study was to investigate for the first time the treatment persistence, efficacy and safety of biologics or small molecules used in 4th or 5th line therapy. METHODS: We reviewed all consecutive patients with IBD treated at the Nancy University Hospital between July 2022 and April 2023 with the 4th or 5th line treatment for at least three months. The primary outcome was to assess the persistence rate of 4th and 5th line therapy. RESULTS: We enrolled 82 patients with IBD (4th line: 44; 5th line: 38). On Kaplan-Meier analysis, the duration of risankizumab, ustekinumab or vedolizumab therapy did not differ significantly (p > 0.05) as 4th and 5th line treatment. The restricted mean survival time analysis showed that the persistence rate of risankizumab was the highest as 4th line therapy (risankizumab vs. vedolizumab: 36.0 and 29.4 weeks, respectively, p = 0.008; risankizumab vs. ustekinumab: 36.0 and 32.8 weeks, respectively, p = 0.035). In multivariate regression, Crohn's disease diagnosis (Odd ratio 4.6; 95% confidence interval 1.7-12.4) was significantly associated with treatment persistence. CONCLUSION: In this first real-world setting, risankizumab could have a longer persistence rate as 4th line treatment for IBD than other agents. Persistence of biological agents was greater in Crohn's disease than in ulcerative colitis. More studies are needed to compare treatment efficacy in patients with difficult-to-treat IBD.

An update on the safety of long-term vedolizumab use in inflammatory bowel disease.

INTRODUCTION: Vedolizumab (Entyvio) is a humanized monoclonal antibody that disrupts the interaction between α4ß7 integrin on circulating T-lymphocytes and MAdCAM-1 on the vascular endothelium to prevent their egress to sites of gut inflammation. It has proven therapeutic efficacy for the treatment of moderate-to-severe Crohn's disease, ulcerative colitis, and pouchitis. AREAS COVERED: This narrative review assesses the safety profile of vedolizumab from the registration trial programs, open-label extension studies, observational real-world data, and pooled safety analyses. This includes an evaluation of the long-term overall safety in special populations typically underrepresented in clinical trials. EXPERT OPINION: Vedolizumab is an effective therapy for inflammatory bowel disease with a well-established safety profile. No unexpected long-term safety signals have been identified. Safety data in pregnancy, in pediatric and elderly populations, in patients undergoing surgery, and in patients with a prior history of cancer are reassuring. Due to its safety merits, we propose that vedolizumab is an excellent candidate for advanced combination treatment with an anti-cytokine approach using another biologic or novel small molecule inhibitor. This is important in patients with medically refractory IBD, in patients at high risk of developing disease-related complications, or in patients with concomitant uncontrolled immune-mediated inflammatory diseases.

Stemming the tide with ileocecal Crohn's disease: when is pharmacotherapy enough?

INTRODUCTION: Crohn's disease (CD) mostly affects the terminal ileum and ileocecal region and up to 80% of patients end up requiring surgery. Previously reserved for complicated or refractory forms, surgery is now considered as an alternative to medical treatment in localized ileocecal disease. AREAS COVERED: This review examines factors associated with response to medical treatment and those associated with the need for surgery in ileocecal CD to identify the patients' profile for whom pharmacotherapy might be enough. Factors associated with the recurrence and the postoperative complications are also reviewed to help the clinician identify patients for whom medical therapy might be preferred. EXPERT'S OPINION: LIR!C study long-term follow-up data show that 38% of infliximab-treated patients were still treated with infliximab at the end of their follow-up, while 14% had switched to another biologic or had received immunomodulator or corticosteroid and 48% had CD-related surgery. Only the combination with an immunomodulator was associated with a greater likelihood of continuing infliximab. Patients with ileocecal CD for whom pharmacotherapy might be sufficient are probably those with no risk factors for CD-related surgery.In addition, patients with high risk of recurrence or of post-operative complications may benefit more from medical treatment than from surgery.

Food avoidance and fasting in patients with inflammatory bowel disease: Experience from the Nancy IBD nutrition clinic.

BACKGROUND: Patients with inflammatory bowel disease (IBD) consider that their diet is important for controlling symptoms and frequently ask their physician for additional guidance on this matter. The objectives of the present study of patients with IBD were to characterize the prevalence of exclusion diets and fasting and to identify associated risk factors. METHODS: Using an anonymous questionnaire, we screened patients attending our IBD nutrition clinic between November 2021 and April 2022 for exclusion diets. The avoidance of a food category completely was defined as total exclusion and avoidance most of the time was defined as partial exclusion. We also asked patients whether they fasted totally, intermittently, or partially. RESULT: A total of 434 patients with IBD were included. On inclusion, 159 patients (36.6%) totally excluded at least one food category and 271 (62.4%) partially excluded at least one food. Intermittent, total, or partial fasting was reported by 30.8% of the patients. Disease activity (odds ratio (OR) [95% confidence interval] = 1.7 [1.1-2.7], p = 0.0130) and treatment with a small-molecule or an investigational drug (OR = 4.0 [1.5-10.6], p = 0.0059) were independently associated with an exclusion diet. A history of stenosis (OR = 2.0 [1.2-3.2], p = 0.0063) and active disease (OR = 1.9 [1.2-3.1], p = 0.0059) were associated with fasting. CONCLUSION: In this real-world study, approximately two-thirds of our patients with IBD reported the partial or total exclusion of at least one food category and one third reported fasting. A systematic nutritional evaluation might improve clinical management and quality of care for patients with IBD both Crohn's disease and ulcerative colitis.

Identification of circulating biomarkers of Crohn's disease and spondyloarthritis using Fourier transform infrared spectroscopy.

Crohn's disease (CD) and spondyloarthritis (SpA) are two inflammatory diseases sharing many common features (genetic polymorphism, armamentarium). Both diseases lack diagnostic markers of certainty. While the diagnosis of CD is made by a combination of clinical, and biological criteria, the diagnosis of SpA may take several years to be confirmed. Based on the hypothesis that CD and SpA alter the biochemical profile of plasma, the objective of this study was to evaluate the analytical capability of Fourier transform infrared spectroscopy (FTIR) in identifying spectral biomarkers. Plasma from 104 patients was analyzed. After data processing of the spectra by Extended Multiplicative Signal Correction and linear discriminant analysis, we demonstrated that it was possible to distinguish CD and SpA from controls with an accuracy of 97% and 85% respectively. Spectral differences were mainly associated with proteins and lipids. This study showed that FTIR analysis is efficient to identify plasma biosignatures specific to CD or SpA.

Available Methods for Benefit-risk Assessment: Lessons for Inflammatory Bowel Disease Drugs.

BACKGROUND AND AIMS: Medical treatment for inflammatory bowel disease has advanced significantly over the two past decades. The advent of biologics and small molecules has revolutionised outcomes for patients with inflammatory bowel disease. Knowledge of drug pharmacology, indications, and adverse events is essential to ensure the best clinical care while minimising toxicity. Our aim was to review the literature on current methods of benefit-risk assessment, and consider their practical applicability to inflammatory bowel disease. METHODS: A literature search was conducted to investigate studies documenting benefit-risk assessment. RESULTS: Several structured frameworks and quantitative methodologies have been developed to evaluate benefit-risk profiles of drugs in a more comprehensive and consistent framework. Quantitative methods integrate benefit and risk outcome measures or incorporate preference weights for benefit and risk criteria into the evaluation. Incorporation of preference weights from patients is an essential aspect of quantitative benefit-risk assessment. Benefit-risk assessment is still evolving in inflammatory bowel disease. CONCLUSIONS: The risks and benefits of each medical therapy must be discussed with the patient and a shared decision-making process is recommended. Future initiatives should be developed to perform a benefit-risk assessment considering the characteristics of inflammatory bowel disease drugs.

Comparative Safety of Ustekinumab and Vedolizumab in Older Patients with Inflammatory Bowel Disease: A Bicentric Cohort Study.

Introduction: Data about the safety of vedolizumab and ustekinumab are lacking in older patients with inflammatory bowel disease. The objective was to compare the safety of vedolizumab and ustekinumab therapies in older patients (>60 years) with inflammatory bowel disease. Methods: This retrospective study included patients with Crohn's disease or ulcerative colitis initiating vedolizumab, ustekinumab or anti-TNF therapy at >60 years of age. We examined the occurrence of adverse events within one year after therapy. Results: This study included 182 patients: 53 were treated with vedolizumab (22 patients with Crohn's disease and 31 with ulcerative colitis), 31 with ustekinumab (30 Crohn's disease and one ulcerative colitis) and 98 with anti-TNF (63 Crohn's disease and 35 ulcerative colitis). At one year, there was no difference in terms of safety in patients with Crohn's disease between vedolizumab and ustekinumab considering the number of adverse events per year of follow-up (p = 0.258). For ulcerative colitis and Crohn's disease, the occurrence of adverse events per year of follow-up was similar between vedolizumab and anti-TNF (p = 0.274 and p = 0.876, respectively). Conclusions: Safety was similar between vedolizumab and ustekinumab in older patients with inflammatory bowel disease.

Inflammatory Bowel Disease Patients' Acceptance for Switching from Intravenous Infliximab or Vedolizumab to Subcutaneous Formulation: The Nancy Experience.

BACKGROUND: Subcutaneous infliximab and vedolizumab formulations have been developed for maintenance therapy in inflammatory bowel disease. The objective of this study was to explore the inflammatory bowel disease patient's acceptance for switching from intravenous infliximab or vedolizumab to subcutaneous, as well as to describe the causes of refusal or, conversely, the factors associated with acceptance. METHODS: Patients were prospectively recruited between June 2021 and March 2022 during their infusion of infliximab or vedolizumab in the Medical Day Hospital of Nancy University Hospital. Adult patients with an established diagnosis of inflammatory bowel disease in clinical remission were eligible for inclusion in this study if they had been treated with intravenous infliximab or vedolizumab for at least six months. RESULTS: One hundred and thirty patients were included in this study. Thirty-six patients (27.7%) received vedolizumab and ninety-four patients (72.3%) received infliximab. Median duration of treatment at inclusion was 7.0 years [3.0-11.0]. In this cohort, 77.7% of patients accepted the switch from intravenous infliximab or vedolizumab to subcutaneous. The main reasons for patient's refusal for switching from intravenous to subcutaneous formulation were fear of loss of efficacy, a more spaced-out medical follow-up, increased frequency of administration, and self-administered injection. A short duration of treatment was associated with a high switch acceptance rate (odd ratio (OR) (95% confidence interval (CI)) = 0.9 (0.8-0.9); p = 0.0002). CONCLUSION: A large majority of the patients included accepted the switch of their treatment with infliximab or vedolizumab from the intravenous form to the subcutaneous form. This study identified one predictor influencing the acceptance rate in inflammatory bowel disease population: short treatment duration. Subcutaneous infliximab and vedolizumab hold potential for greater patient flexibility by self-administration, reducing travel and hospital attendance for infusion.

Landscape of new drugs and targets in inflammatory bowel disease.

Although the therapeutic armamentarium of Inflammatory bowel diseases (IBD) physicians has expanded rapidly in recent years, a proportion of patients remain with a suboptimal response to medical treatment due to primary no response, loss of response or intolerance to currently available drugs. Our growing knowledges of IBD pathophysiology has led to the development of a multitude of new therapies over time, which may, 1 day, be able to address this unmet medical need. This review aims to provide physicians an update of emerging therapies in IBD by focusing on drugs currently in phase 3 clinical trials. Among the most promising molecules are anti-IL-23, JAK-inhibitors, anti-integrins and S1P modulators. While the results in terms of efficacy and safety are fairly clear for some classes, the question of safety remains more uncertain for other classes. Molecules at a more preliminary stage of development (phase 1 and 2), one of which may 1 day offer an optimal benefit-risk ratio, will also be presented as well as their respective mechanisms of action.

Ocular Manifestations in Patients with Inflammatory Bowel Disease in the Biologics Era.

Background: Extra-intestinal manifestations are frequent in inflammatory bowel disease (IBD). Ocular disorders are generally under diagnosed as they are challenging diagnosis. Aims: We assessed the prevalence of ophthalmological manifestations in patients with IBD, and investigated characteristics associated with ocular manifestations. Methods: We performed a retrospective study including patients followed for IBD and had an ophthalmologic visit from January 2013 to July 2020, among 1432 patients followed during this period. Two groups were considered: the first group included patients whose an ocular diagnosis was considered as "related to IBD", and the second group including patients whose an ocular diagnosis was considered "not related to IBD". Results: Among 1432 patients with IBD, eighty-seven (6.1%) patients had an ophthalmologic visit. Fifty-three patients (3.7%) were considered to have an ocular extra-intestinal manifestation or an iatrogenic effect of IBD treatment, and 34 diagnoses (2.4%) were considered not related to IBD. Inflammatory surface pathologies were the most frequent (33.2%), including 15 patients with dry eye (17.2%), 9 with blepharitis (10.3%), and 5 with chalazions (meibomian cyst) (5.7%). Uveitis was diagnosed in 13 patients (14.9%), episcleritis in 5 patients (5.7%), and scleritis in 2 patients (2.3%). Characteristics of patients with an ophthalmological diagnosis "related to IBD" versus "not related to IBD" were not statistically different. Conclusion: In our cohort, less than 5% of patients had ophthalmological extra-intestinal manifestation. The most frequent ocular diagnosis were dry eye and uveitis. No disease characteristics of IBD were found to be associated with ocular manifestations.

Impact of the Exposome on the Epigenome in Inflammatory Bowel Disease Patients and Animal Models.

Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gastrointestinal tract that encompass two main phenotypes, namely Crohn's disease and ulcerative colitis. These conditions occur in genetically predisposed individuals in response to environmental factors. Epigenetics, acting by DNA methylation, post-translational histones modifications or by non-coding RNAs, could explain how the exposome (or all environmental influences over the life course, from conception to death) could influence the gene expression to contribute to intestinal inflammation. We performed a scoping search using Medline to identify all the elements of the exposome that may play a role in intestinal inflammation through epigenetic modifications, as well as the underlying mechanisms. The environmental factors epigenetically influencing the occurrence of intestinal inflammation are the maternal lifestyle (mainly diet, the occurrence of infection during pregnancy and smoking); breastfeeding; microbiota; diet (including a low-fiber diet, high-fat diet and deficiency in micronutrients); smoking habits, vitamin D and drugs (e.g., IBD treatments, antibiotics and probiotics). Influenced by both microbiota and diet, short-chain fatty acids are gut microbiota-derived metabolites resulting from the anaerobic fermentation of non-digestible dietary fibers, playing an epigenetically mediated role in the integrity of the epithelial barrier and in the defense against invading microorganisms. Although the impact of some environmental factors has been identified, the exposome-induced epimutations in IBD remain a largely underexplored field. How these environmental exposures induce epigenetic modifications (in terms of duration, frequency and the timing at which they occur) and how other environmental factors associated with IBD modulate epigenetics deserve to be further investigated.

Faecal incontinence in inflammatory bowel disease: The Nancy experience.

BACKGROUND: Faecal incontinence (FI) is a disabling condition in patients with inflammatory bowel disease (IBD). The diagnosis of FI is not easy as patients are reluctant to report this embarrassing symptom. The objectives of this study were to characterize the prevalence of FI in IBD patients using available scoring systems, and to identify associated risk factors. METHODS: A FI clinic was implemented in routine practice between January 2020 and April 2021. FI was defined as a Wexner score ≥5. Factors associated with FI were analyzed. RESULTS: A total of 319 consecutive patients with IBD were included. The prevalence of FI was 16.4% (53/319). Age >45 years at inclusion (Odd ratio (OR)=3.33, Confidence interval (CI) 95% 1.40-7.94), diarrhea (three stools at least per day) (OR=2.94, CI 95% 1.16-7.45), stool consistency according to the Bristol stool chart (OR=2.23, CI 95% 1.00-4.99), and abdominal pain (OR=2.24, CI 95% 1.10-4.53) were independently associated with FI in a multivariate model analysis. CONCLUSIONS: Approximately one fifth of IBD patients reported FI in this real-world cohort, using an available scoring system. Increased age, diarrhea, stool consistency according to the Bristol stool chart, and abdominal pain were associated with FI. A systematic screening of FI would allow a better management of this disabling condition.

Gastroenterological safety of IL-17 inhibitors: a systematic literature review.

INTRODUCTION: Interleukin 17 is a proinflammatory cytokine considered to play a significant role in the immunopathogenesis of many chronic immune-mediated disorders. Interleukin 17 inhibitors provide an excellent treatment option for patients with psoriasis, psoriatic arthritis, or ankylosing spondylitis. However, Interleukin 17 inhibitors have been suspected of worsening or triggering new-onset inflammatory bowel disease. AREAS COVERED: A literature search was conducted until March 2021 to investigate reporting prevalence, and characteristics of all gastroenterological adverse events in patients treated with Interleukin 17 inhibitors. One hundred and six clinical randomized trials were included, involving 40,053 patients. Inflammatory bowel disease cases were reported in 0.4% of patients exposed to Interleukin 17 inhibitors. The most frequent other gastrointestinal adverse events were diarrhea (2.5%), nausea or vomiting (0.7%), and gastroenteritis (0.2%). Sixty-one uncontrolled or retrospective studies were included, involving 16,791 patients. Sixty (0.36%) inflammatory bowel disease cases were reported, 0.6% of patients reported other gastrointestinal adverse events. EXPERT OPINION: Interleukin 17 inhibitors are safe and effective in the treatment of psoriasis, psoriatic arthritis, and ankylosing spondylitis. Low incidence rate of developing new-onset inflammatory bowel disease or exacerbating preexisting inflammatory bowel disease with anti-IL-17 agents has been reported. Clinicians should be aware of the possibility of these concerns when considering this therapy.

[Reforming Biosciences and Health Research: Part I, Funding]. / Rapport 21-06. Réformer la recherche en sciences biologiques et en santé : partie I, le financement.

The COVID-19 pandemic occurred in the context of a dramatic decline in support for biological and health research in France. An analysis of resources allocated to this sector shows that the credits in 2020 correspond to only 17.2 % of the total credits allocated to research, the lowest ratio inat least 15 years. Another weakness in the system of support for hospital research is the way funds from the health insurance system are allocated. To bring it into line with international best practices, the task of allocating these funds should be entrusted to a "Hospital Research Orientation Council", which should also be involved in the implementation of national research programming. Another article deals with the organization of research. Recommendations are also made to improve the functioning of the research system at the local level, particularly in university hospitals, and at the national level.

Incidence of and Risk Factors for Colorectal Strictures in Ulcerative Colitis: A Multicenter Study.

BACKGROUND & AIMS: Ulcerative colitis (UC) is increasingly recognized as a progressive disease and patients with long-standing disease can develop colorectal stricture. Few data about its incidence in UC are available, while risk factors for colorectal strictures in UC remain to be determined. We assessed the incidence of and risk factors for developing colorectal strictures in a large UC population. METHODS: All adult patients followed at Nancy University hospital and at the centre hospitalier de Luxembourg for UC, between January 2004 and July 2019, were eligible for inclusion in this multicenter retrospective cohort study. RESULTS: A total of 439 patients with UC were included. Median follow-up duration was 9.6 years. Incidence of colorectal stricture was 3.6%. The cumulative probability of developing this complication was 1% at 5 years and 2.3% at 10 years. Median age at stricture diagnosis was 47.9 years (41.0; 63.0), and median time from UC diagnosis to onset of stricture was 11.5 years (5; 15.3). Montreal A3 classification (age > 40 years) (P = .008) and steroids use (HR = 4.1; 95% CI, 1.1-16.1) were independent risk factors for stricture, whereas mesalamine-treated patients carried a lower risk (HR = 0.3; 95% CI, 0.1-0.9). Dysplasia was found in 6 patients with strictures (42.9%) and among them 5 developed a colorectal cancer (33.3%). CONCLUSIONS: Patients with Montreal A3 classification and those exposed to steroids have a higher risk for strictures, while use of mesalamine lowers this risk. These factors should be assessed in daily clinical practice to prevent stricture occurrence in these patients.

IL-17 Inhibitors and Inflammatory Bowel Diseases: A Postmarketing Study in Vigibase.

Several gastrointestinal symptoms and chronic inflammatory bowel diseases (IBDs) have been reported after therapy with IL-17 inhibitors. To date, however, no study has shown a clear association between these drugs and IBD onset. We searched on Vigibase, the worldwide pharmacovigilance database, to investigate reporting prevalence, characteristics, and prognosis of all gastroenterological adverse events in patients treated with IL-17 inhibitors. In total, 1,129 gastrointestinal Individual Case Safety Reports (ICSRs) were identified, including 850 IBD (42.5% Crohn's disease, 31.9% ulcerative colitis, and 25.6% undifferentiated IBD) and 279 colitis (mainly undifferentiated colitis (79.2%), and microscopic colitis (10.4%)). ICSRs were associated with secukinumab (SEC, 83.6%) or ixekizumab (IXE, 16.3%), whereas only one colitis occurred with brodalumab (0.1%). Most IBD and colitis cases were detected within 6 months from therapy start in both the SEC (68.8% and 73.5%) and IXE groups (100% and 66.7%). Patients' outcomes were reported in 428 ICSRs (37.9%). Complete or ongoing recovery from symptoms was detected in about two-thirds of patients experiencing IBD (59.5%) or colitis (64.2%), whereas in the other cases, there was no recovery (33.9% and 29.5%) or there were sequelae (5.4% and 4.2%). Fatal events occurred in four patients (1.2%) in the IBD group (3 after SEC and on1e with IXE) and two SEC-treated subjects in the colitis group (2.1%). Treatment with IL-17 inhibitors is associated with a relevant number of exacerbations and new onset of IBD and colitis. Careful evaluation of gastrointestinal symptoms and the monitoring of intestinal inflammatory biomarkers should be recommended before prescribing these drugs.

Low Back Pain and Sacroiliitis on Cross-Sectional Abdominal Imaging for Axial Spondyloarthritis Diagnosis in Inflammatory Bowel Diseases.

BACKGROUND: Joint damage is the most frequent extraintestinal manifestation in inflammatory bowel disease (IBD). AIMS: The aim of the study was to assess the value of low back pain (LBP) associated with sacroiliitis on abdominal imaging for the diagnosis of spondyloarthritis (SpA) in IBD. METHODS: We used a questionnaire assessing rheumatological symptoms for all patients with abdominal computed tomography (CT) and magnetic resonance enterography (MRE). Sacroiliitis was assessed on available CT and MRE. Patients were classified as axial SpA according to the Assessment of SpondyloArthritis International Society criteria. RESULTS: Fifty-one patients completed the questionnaire and performed both exams. LBP was present in 27 patients (52.9%), and 10 (19.6%) had an inflammatory component. Sacroiliitis was reported in 12 patients (23.5%), and 6 of them suffered from LBP. Among the 20 patients referred to the rheumatologist, 11 patients suffered from LBP. One patient was HLA-B27 positive and presented sacroiliitis. For the last 10 patients, none of them had a sacroiliitis, and 2 patients were negative for HLA-B27. CONCLUSION: An axial SpA has been diagnosed in 11.8% of IBD patients undergoing cross-sectional imaging, whereas one-fifth had inflammatory LBP, and sacroiliitis was observed in one-quarter of them. To optimize the diagnosis of axial SpA, HLA-B27 testing might be required for patients with both IBD and LBP, but this will require further investigation before its implementation in routine practice.