Outcome of Biological Therapies and Small Molecules in Ulcerative Proctitis: A Belgian Multicenter Cohort Study.

BACKGROUND & AIMS: Several advanced therapies (biologic therapies and small molecules) have been approved for the treatment of moderate-to-severe ulcerative colitis. The registration trials for these agents typically excluded patients with isolated proctitis, leaving an evidence gap. We evaluated efficacy and safety of advanced therapies in patients with ulcerative proctitis (UP). METHODS: This multicenter retrospective cohort study included consecutive patients with active UP (Mayo endoscopy subscore of ≥2, rectal inflammation up to 15 cm) initiating advanced therapy, after failing conventional therapy. The primary end point was short-term steroid-free clinical remission (total Mayo score ≤2 with no individual subscore >1). In addition, drug persistence and relapse-free and colectomy-free survival were assessed. Both binary logistic and Cox regression analyses were performed. RESULTS: In total, 167 consecutive patients (52.0% female; median age 41.0 years; 82.0% bionaive) underwent 223 courses of therapy for UP (38 adalimumab, 14 golimumab, 54 infliximab, 9 ustekinumab, 99 vedolizumab, 9 tofacitinib). The primary end point was achieved with 36.3% of the treatment courses, and based on multivariate analysis, more commonly attained in bionaive patients (P = .001), patients treated with vedolizumab (P = .001), patients with moderate endoscopic disease activity (P = .002), and a body mass index <25 kg/m2 (P = .018). Drug persistence was significantly higher in patients treated with vedolizumab (P < .001) and patients with a shorter disease duration (P = .006). No new safety signals were observed. CONCLUSIONS: Advanced therapies are also efficacious and safe in patients with ulcerative colitis limited to the rectum. Therefore, the inclusion of patients with UP in future randomized-controlled trials should be considered.

Dysbiosis and Associated Stool Features Improve Prediction of Response to Biological Therapy in Inflammatory Bowel Disease.

BACKGROUND & AIMS: Dysbiosis of the gut microbiota is considered a key contributor to inflammatory bowel disease (IBD) etiology. Here, we investigated potential associations between microbiota composition and the outcomes to biological therapies. METHODS: The study prospectively recruited 296 patients with active IBD (203 with Crohn's disease, 93 with ulcerative colitis) initiating biological therapy. Quantitative microbiome profiles of pretreatment and posttreatment fecal samples were obtained combining flow cytometry with 16S amplicon sequencing. Therapeutic response was assessed by endoscopy, patient-reported outcomes, and changes in fecal calprotectin. The effect of therapy on microbiome variation was evaluated using constrained ordination methods. Prediction of therapy outcome was performed using logistic regression with 5-fold cross-validation. RESULTS: At baseline, 65.9% of patients carried the dysbiotic Bacteroides2 (Bact2) enterotype, with a significantly higher prevalence among patients with ileal involvement (76.8%). Microbiome variation was associated with the choice of biological therapy rather than with therapeutic outcome. Only anti-tumor necrosis factor-α treatment resulted in a microbiome shift away from Bact2, concomitant with an increase in microbial load and butyrogen abundances and a decrease in potentially opportunistic Veillonella. Remission rates for patients hosting Bact2 at baseline were significantly higher with anti-tumor necrosis factor-α than with vedolizumab (65.1% vs 35.2%). A prediction model, based on anthropometrics and clinical data, stool features (microbial load, moisture, and calprotectin), and Bact2 detection predicted treatment outcome with 73.9% accuracy for specific biological therapies. CONCLUSION: Fecal characterization based on microbial load, moisture content, calprotectin concentration, and enterotyping may aid in the therapeutic choice of biological therapy in IBD.

The cost of inflammatory bowel disease in high-income settings: a Lancet Gastroenterology & Hepatology Commission.

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.

Holistic healthcare in inflammatory bowel disease: time for patient-centric approaches?

Inflammatory bowel disease (IBD) is an emerging global disease characterised by chronic inflammation of the gastrointestinal tract. However, IBD is also manifested by several extraintestinal symptoms which, along with the intestinal symptoms, impact on the mental and emotional well-being of patients. Despite therapeutic advancements, only one-third of the diagnosed patients receiving approved medical treatments achieve short-term to medium-term remission. Consequently, patients who do not get successfully treated might resort to using complementary and alternative approaches to manage their symptoms, with or without consulting their treating clinician. Despite their possible potential, such approaches have various risks stemming from unknown adverse reactions and possible interference with medically approved therapies. In this study, we present the results of a well-performed literature review where we included randomised clinical trials which have assessed the efficacy of complementary approaches and dietary therapy on at least one of the following four outcomes: clinical remission, endoscopic remission, modulation of molecular biomarkers or quality of life metrics. By pointing out intraoutcome and interoutcome concordance, we identified possible candidates for clinical adoption and further study in larger randomised clinical trials covering the broad spectrum of IBD heterogeneity. We finally proposed a patient-centric clinical care model and a series of recommendations for stakeholders, with special attention to complementary approaches and dietary strategies, aimed at achieving holistic remission.

Safety of sequential biological therapy in inflammatory bowel disease: results from a tertiary referral centre.

BACKGROUND: Biologicals represent the cornerstone of treatment for moderate-to-severe inflammatory bowel diseases (IBD). Many patients cycle between biologicals when encountering loss of response or adverse events. AIM: To assess the occurrence of serious infections and malignancies with exposure to several (classes of) biologicals. METHODS: We performed a retrospective cohort study in a tertiary referral centre including consecutive IBD patients exposed to adalimumab, infliximab, ustekinumab or vedolizumab between 1996 and 2019. All serious infections and malignancies, as well as potential confounders, were accounted for. RESULTS: In total, 1575 patients were included with a median (interquartile range) follow-up of 10 (6-16) years and a duration of biological therapy of 71 (39-112) months. Incidence rates of serious infections were 3.4 per 100 patients' years (PY) in the post-biological setting. Serious infections after biological exposure were associated with systemic steroids in monotherapy (hazard ratio 2.96 [95% confidence interval 1.78-4.93], p < 0.0001), combination therapy of systemic steroids and a biological (2.44 [1.37-4.34], p = 0.002), female gender (1.25 [1.04-1.51], p = 0.02), and prior serious infections in the pre-biological setting (1.42 [1.03-1.96], p = 0.03). Malignancy rates were 1.06 per 100PY in the post-biological setting and increased with older age at biological initiation (1.04 [1.02-1.05], p < 0.0001). The risk for serious infections or malignancies was independent of type and number of biologicals to which the patient was exposed. CONCLUSION: This study shows that the sequential use of biological therapy in IBD does not seem to convey an overall higher risk of serious infections or malignancies, but that underlying more refractory disease seems to increase this risk.

A systems genomics approach to uncover patient-specific pathogenic pathways and proteins in ulcerative colitis.

We describe a precision medicine workflow, the integrated single nucleotide polymorphism network platform (iSNP), designed to determine the mechanisms by which SNPs affect cellular regulatory networks, and how SNP co-occurrences contribute to disease pathogenesis in ulcerative colitis (UC). Using SNP profiles of 378 UC patients we map the regulatory effects of the SNPs to a human signalling network containing protein-protein, miRNA-mRNA and transcription factor binding interactions. With unsupervised clustering algorithms we group these patient-specific networks into four distinct clusters driven by PRKCB, HLA, SNAI1/CEBPB/PTPN1 and VEGFA/XPO5/POLH hubs. The pathway analysis identifies calcium homeostasis, wound healing and cell motility as key processes in UC pathogenesis. Using transcriptomic data from an independent patient cohort, with three complementary validation approaches focusing on the SNP-affected genes, the patient specific modules and affected functions, we confirm the regulatory impact of non-coding SNPs. iSNP identified regulatory effects for disease-associated non-coding SNPs, and by predicting the patient-specific pathogenic processes, we propose a systems-level way to stratify patients.

Rates of Postoperative Recurrence of Crohn's Disease and Effects of Immunosuppressive and Biologic Therapies.

BACKGROUND & AIMS: The Rutgeerts' scoring system is used to evaluate patients with Crohn's disease (CD) following ileocolic resection, based on endoscopic findings at the anastomosis and in the neoterminal ileum. We investigated rates of clinical and surgical recurrence of CD after surgery and effect of therapy modification based on post-operative endoscopic findings. METHODS: We collected data from 365 adults with CD (20% with Rutgeerts' score i0, 10% with score i1, 49% with score i2, 12% with score i3, 9% with score i4) who underwent ileocolonoscopy within 12 months of ileocolic resection with anastomosis from 2000 through 2013 at 2 centers in Belgium and France. Patients were followed for 3 y or more after the ileocolonoscopy. Clinical post-operative recurrence (POR) was defined as occurrence of CD symptoms along with biologic, radiologic, and/or endoscopic features of disease activity; modified surgical POR was defined as either an endoscopic or surgical intervention. RESULTS: After a median follow-up time of 88 months, 48% of patients had clinical POR and 26% had modified surgical POR. Rates of survival without clinical POR or a modified surgical POR were lower in patients with Rutgeerts' scores of i2, i3, or i4 compared to patients with scores of i0 or i1 (P < .001 and P = .02). New immunosuppressant or biological therapy was initiated following endoscopy in 129/254 patients (51%) with Rutgeerts' score of i2, i3, or i4 vs 7/111 patients (6%) with scores of i0 or i1 (odds ratio for new therapy, 14.9; 95% CI, 7.1-36.8; P < .001). A modest decrease in risk of clinical POR was observed for patients with Rutgeerts scores of i3 or i4 after initiation of immunosuppressive or biological therapy based on endoscopic findings (Breslow P = .03), but this was not observed for patients with scores of i2 (Breslow P = .46). CONCLUSIONS: Use of immunosuppressants and tumor necrosis factor antagonists to treat patients with an asymptomatic endoscopic post-operative recurrence of CD did not reduce long-term risk of clinical recurrence in patients with Rutgeerts' scores of i2, but it had a small effect in patients with scores of i3 or i4.

Development and feasibility of a telemonitoring tool with full integration in the electronic medical record: a proof of concept study for patients with inflammatory bowel disease in remission on biological therapy.

Objectives: Telemonitoring can be implemented to enhance disease monitoring and ultimately reduce the number of outpatient visits and associated costs. We developed an in house IBD mobile app and established a proof of concept study to demonstrate the effectiveness and accuracy of the telemonitoring tool for monitoring of disease activity.Methods: An IBD mobile app was designed through close collaboration between the Information Technology and Gastroenterology department of University Hospitals of Leuven. The study was proposed to all patients in remission under stable biological therapy visiting the outpatient clinic. During one-year follow-up, patients completed weekly and monthly questionnaires on their mobile device or on a website. Entered data were directly sent to the electronic medical record. Predefined red flags or alerts, generated by the answers to the questionnaires, were monitored daily.Results: The pilot study in 45 patients demonstrated accurate monitoring of disease activity with fast intervention during flares. During the 12-months follow-up period, an alert for disease activity was generated for 9 different patients out of 1296 completions of the questionnaire. Symptoms resolved spontaneously in 8 patients. One patient reported consecutive PRO-2 increase, endoscopy confirmed an IBD flare and therapy was switched. For the remaining 36 included patients, no alerts indicating disease activity increase were reported. Median compliance to all weekly and monthly questionnaires during 1 year was 52% (IQR: 24-91).Conclusions: We developed the mynexuzhealth IBD app with full integration in the electronic medical record. The app enabled continuous remote monitoring and showed accurate detection of flares.

Long-term Clinical Effectiveness of Ustekinumab in Patients with Crohn's Disease Who Failed Biologic Therapies: A National Cohort Study.

BACKGROUND: Ustekinumab [UST] was recently approved in Europe for the treatment of moderate to severe Crohn's disease [CD]. Long-term real-world data are currently scarce for CD patients previously exposed to several biologics. METHODS: This is an observational, national, retrospective multicentre study. Patients received intravenous UST ~6 mg/kg at baseline, with 90 mg subcutaneously thereafter every 8 weeks. Response and remission rates were assessed at Weeks 8, 16, and 52. RESULTS: Data from 152 patients were analysed. All patients were exposed to at least one anti-TNFα agent, with 69.7% were exposed to even two anti-TNFα and vedolizumab. After 1 year, 42.1% and 25.7% of patients had experienced clinical response and clinical remission, respectively, and 38.8% and 24.3% had achieved steroid-free clinical response and remission, respectively; 38.8% of patients discontinued therapy during the 12 months of follow-up. Colonic location was predictive of clinical response at 1 year, and low body mass index [BMI] at baseline was a negative predictor of clinical remission. Resolution of arthralgia was associated with clinical response over time. De novo arthralgia was reported by 17.9% of patients at Week 8 and 13.5% of patients at Week 52. No impact of UST on arthralgia was observed in patients with concomitant ankylosing spondylitis [n = 17]. Others adverse events were reported in 7.2% of patients. CONCLUSIONS: This real-world cohort study confirms the effectiveness of UST in CD patients previously exposed to several biologics. Ustekinumab was well tolerated with respect to adverse events. PODCAST: This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast.

Effects of introduction of an inflammatory bowel disease nurse position on the quality of delivered care.

BACKGROUND AND AIMS: Inflammatory bowel diseases (IBDs) are chronic gastrointestinal conditions requiring long-term outpatient follow-up, ideally by a dedicated, multidisciplinary team. In this team, the IBD nurse is the key point of access for education, advice, and support. We investigated the effect of the introduction of an IBD nurse on the quality of care delivered. METHODS: In September 2014, an IBD nurse position was instituted in our tertiary referral center. All contacts and outcomes were prospectively recorded over a 12-month period using a logbook kept by the nurse. RESULTS: Between September 2014 and August 2015, 1313 patient contacts were recorded (42% men, median age: 38 years, 72% Crohn's disease, 83% on immunosuppressive therapy). The contacts increased with time: Q1 (September-November 2014): 144, Q2: 322, Q3: 477, and Q4: 370. Most of the contacts were assigned to scheduling of follow-up (316/1420), start of new therapy (173/1420), therapy follow-up (313/1420), and providing disease information (227/1420). In addition, 134 patients contacted the IBD nurse for flare management and a smaller number for administrative support, psychosocial support, and questions about side effects. During the study period, 30 emergency room and 133 unscheduled outpatient visits could be avoided through the intervention of the IBD nurse. A faster access to procedures and other departments could be provided for 136 patients. CONCLUSION: The role of IBD nurses as the first point of contact and counseling is evident from a high volume of nurse-patient interactions. Avoidance of emergency room and unscheduled clinic visits are associated with these contacts.

Biological therapy targeting the IL-23/IL-17 axis in inflammatory bowel disease.

INTRODUCTION: As many inflammatory bowel disease (IBD) patients do not benefit from long-term anti-tumour necrosis factor treatment, new anti-inflammatories are urgently needed. After the discovery of the interleukin (IL) 23/17 axis being pivotal in IBD pathogenesis, many different compounds were developed, targeting different components within this pathway. Areas covered: A literature search to March 2016 was performed to identify the most relevant reports on the role of the IL-23/IL-17 axis in IBD and on the different molecules targeting this pathway. First, the authors briefly summarize the immunology of the IL-23/IL-17 pathway to elucidate the mode of action of all different agents. Second, they describe all different molecules targeting this pathway. Besides discussing efficacy and safety data, they also explore immunogenicity, exposure during pregnancy and pharmacokinetics. Expert opinion: A new era in IBD treatment has recently been initiated: besides immunomodulators and TNF-antagonists, anti-adhesion molecules and monoclonal antibodies targeting the IL-23/IL-17 pathway have been developed. Biomarkers for personalized medicine are urgently needed. This therapeutic (r)evolution will further improve disease-related and patient-reported outcome, though a lot of questions should still be addressed in future years.

Interpreting Registrational Clinical Trials of Biological Therapies in Adults with Inflammatory Bowel Diseases.

BACKGROUND: The use of biologics to treat inflammatory bowel disease is supported by robust randomized controlled trials in both ulcerative colitis and Crohn's disease. Nonetheless, an understanding of the principles of clinical trial design is necessary to extrapolate study findings to clinical practice. METHODS: We conducted a review of inflammatory bowel disease registrational clinical trials of biologics to determine how differences in trial design potentially influence results and interpretation. RESULTS: Registrational trials of biological agents have used diverse patient populations, outcome measures, and designs, which makes comparisons of results among studies difficult. Key differences among trials include patient populations, choice of symptom-based measures or objective outcomes as endpoints, and overall trial design. Additional factors, including analytical methods, can also influence the interpretation of outcomes. CONCLUSIONS: The most robust evidence is derived from comparative effectiveness trials. In the absence of these, clinicians should be aware of the various methodological issues which could impact interpretation of efficacy and safety outcomes, including differences in patient population, study design, and analytic methodology.

Autophagy: a new target or an old strategy for the treatment of Crohn's disease?

In the past 5 years much progress has been made in understanding the molecular basis of Crohn's disease, a multifactorial chronic inflammatory disease of the gastrointestinal tract. Data suggest that hampered autophagy--the major lysosomal pathway for recycling of cytoplasmic material--might contribute to an increased susceptibility to Crohn's disease. Consequently, intense investigations have started to evaluate the potential value of autophagy as a therapeutic target and as a highly needed diagnostic tool. Interestingly, as well as the promising introduction of direct autophagic modulators, several drugs already used in the treatment of Crohn's disease might exert at least part of their effect through the regulation of autophagy. However, whether this phenomenon contributes to or rather counteracts their therapeutic use, remains to be determined and might prove to be highly compound-specific. Here we review the complex and emerging role of autophagy modulation in the battle against Crohn's disease. Moreover, we discuss the potential benefits and deleterious effects of autophagic regulation by both new and clinically used drugs.

Optimizing biologic therapies for inflammatory bowel disease (ulcerative colitis and Crohn's disease).

The introduction of biologic agents and particularly of anti-tumor necrosis factor antibodies dramatically changed the therapeutic algorithm in patients with inflammatory bowel diseases. Although the efficacy of these agents has been demonstrated clearly, optimal treatment strategies are debated. Recent trials advocate the introduction of biologic agents at an early stage to prevent debilitating complications. However, significant adverse events have led to careful selection of patients who will benefit most from long-term treatment with biologic agents. Once on biologic therapy, scheduled maintenance therapy is recommended to minimize the risk of loss of response. Nevertheless, treatment adaptation is frequently necessary in patients who lose response. Interventions encompass strategies to increase drug exposure by increasing the dose or decreasing the dosing interval, or by changing to another biologic agent. Finally, it remains unclear if and when a biologic agent can be stopped in patients with long-standing remission.

Biological therapies for inflammatory bowel diseases.

Crohn's disease and ulcerative colitis are chronic disabling inflammatory bowel diseases (IBDs). Although the causes of IBD are unknown, defects in innate and adaptive immune pathways have been identified and biological therapies that target key molecules have been designed. Infliximab, a chimeric immunoglobulin (Ig)G1 monoclonal antibody to tumor necrosis factor, dramatically improved treatment of patients with Crohn's disease and ulcerative colitis. Infliximab has achieved treatment goals such as mucosal healing and decreasing the need for hospitalizations and surgeries. Although several anti-tumor necrosis factor therapies have been developed, there is a great need for drugs that target other pathways. Natalizumab, an antibody against the integrin alpha4 subunit, blocks leukocyte adhesion and has reached the clinic in the United States but has not been approved in the European Union; other anti-adhesion molecules currently are under development. Additional approaches under clinical development include therapeutics that target cytokines, such as interleukin-12/23, as well as those that block T-cell signaling. The use of recombinant human proteins, including immunoregulatory cytokines and growth factors, has not been successful so far. The efficacy of each therapy must be shown in carefully designed clinical programs. Biological therapies carry a definite safety risk, so their place in treatment algorithms must be defined carefully.

Focus on mechanisms of inflammation in inflammatory bowel disease sites of inhibition: current and future therapies.

Anti-TNF antibodies were the first biologic agents registered to treat patients who have CD and, more recently, patients who have UC. The sequence of events underlying the inflammatory reaction in IBD is extremely complex, however, and involves both the innate and antigen-driven adaptive immune system. Novel therapies are directed at several key players of this cascade. Blockade of T-cell proliferation and activation and inhibition of T-cell cytokines has been most extensively targeted by clinical trials in humans. Inhibition of adhesion molecules and the use of selected growth factors seem to have therapeutic potential. Restoration of regulatory T-cell and dendritic-cell function is still waiting to be explored in clinical trials. Although an increasing number of biologic therapies for IBD are being developed, the discovery of the full spectrum of treatment modalities is only beginning. Often, however, the clinical efficacy of biologic agents is investigated, and for some molecules is established, before mechanisms of action are specifically explored. Eight years after the Food and Drug Administration approved infliximab for the treatment of luminal CD, it is not known how this anti-TNF antibody actually dampens inflammation in IBD. The advent of newer anti-TNF agents is only postponing the answer.

Safety issues with biological therapies for inflammatory bowel disease.

PURPOSE OF REVIEW: The purpose of this review is to summarize recent evidence describing specific complications associated with the use of biological therapy derived from controlled trials and from post-marketing surveillance. RECENT FINDINGS: Biological therapies, particularly anti-tumour necrosis factor antibodies, are increasingly used in patients with Crohn's disease and ulcerative colitis. Some adverse events, such as serious infections, are a consequence of the immunomodulatory effect of biological agents, while other complications, such as the induction of autoimmune phenomena, neurotoxicity and the development of an immune response to engineered proteins, are class or molecule-specific. Although the immunopathogenesis of these side effects is often a matter of debate, they have been observed not only in inflammatory bowel disease, but also in other immune disorders such as rheumatoid arthritis and psoriasis. SUMMARY: The benefits of biological agents clearly outweigh the risks. Nevertheless, they are associated with specific toxicity, and this requires the attention of the clinician.

Emerging biological treatments in inflammatory bowel diseases.

Although the advent of infliximab has changed the treatment paradigm and goals in inflammatory bowel disease, it does not provide a cure for it and recent evidence has demonstrated that the immunogenicity of this chimeric anti-tumor necrosis factor antibody is associated with secondary loss of response and intolerance. In ulcerative colitis the efficacy of infliximab was demonstrated in two large clinical trials, but long-term maintenance efficacy data are lacking. Novel biological agents have entered clinical development and pioneering trials have been reported in the last 2 years. For Crohn's disease the fully human IgG1 anti-tumor necrosis factor monoclonal adalimumab, and the humanized anti-alpha4-integrin IgG4 antibody, natalizumab have yielded the most promising results in controlled trials, but also agents inhibiting the crucial interleukin-12/interferon-gamma feedback loop suggest therapeutic potential. For severe ulcerative colitis infliximab has been shown to be an effective rescue treatment and the anti-T-cell CD3 antibody has shown promising open-label results. Crucial in the development of novel biological agents, however, is the benefit:risk ratio. As illustrated by unexpected but devastating brain infections with anti-adhesion molecules, clinicians should be aware that the powerful immunomodulatory capacity of biologicals necessitates a rigorous safety follow-up.