Intestinal microbiome dysbiosis has been consistently described in patients with IBD. In the last decades,
, and the adherent-invasive
(AIEC) pathotype in particular, has been implicated in the ...pathogenesis of IBD. Since the discovery of AIEC, two decades ago, progress has been made in unravelling these bacteria characteristics and its interaction with the gut immune system. The mechanisms of adhesion of AIEC to intestinal epithelial cells (via FimH and cell adhesion molecule 6) and its ability to escape autophagy when inside macrophages are reviewed here. We also explore the existing data on the prevalence of AIEC in patients with Crohn's disease and UC, and the association between the presence of AIEC and disease location, activity and postoperative recurrence. Finally, we highlight potential therapeutic strategies targeting AIEC colonisation of gut mucosa, including the use of phage therapy, bacteriocins and antiadhesive molecules. These strategies may open new avenues for the prevention and treatment of IBD in the future.
Summary
Background
There is an increasing body of evidence showing that earlier use of biologics improves clinical outcomes in Crohn's disease (CD).
Aim
To perform a systematic review and ...meta‐analysis to assess the impact of early biologic use in the treatment of CD.
Methods
PubMed and Embase databases were searched for English language papers and conference s published through April 30, 2019. Studies were selected for inclusion if patients initiated biologics within 2 years of a CD diagnosis or if earlier biologics use (top‐down) was compared with a conventional step‐up strategy. Random‐effects meta‐analyses were conducted to compare clinical remission (CR), relapse and endoscopic healing rates between early biologic treatment (<2 years of disease duration or top‐down treatment strategy) and late/conventional treatment (biologic use after >2 years of disease duration or conventional step‐up treatment strategy).
Results
A total of 3069 records were identified, of which 47 references met the selection criteria for systematic review. A total of 18 471 patients were studied, with a median follow‐up of 64 weeks (range 10‐416). Meta‐analysis found that early use of biologics was associated with higher rates of clinical remission (OR 2.10 95% CI: 1.69‐2.60, n = 2763, P < .00001), lower relapse rates (OR 0.31 95% CI: 0.14‐0.68, n = 596, P = .003) and higher mucosal healing rates (OR 2.37 95% CI: 1.78‐3.16, n = 994, P < .00001) compared with late/conventional management.
Conclusions
Early biologic treatment is associated with improved clinical outcomes in both adult and paediatric CD patients, not only in prospective clinical trials but also in real‐world settings.
The traditional management of Crohn's disease, which is based on progressive, step-wise treatment intensification with re-evaluation of response according to symptoms, does not improve long-term ...outcomes of Crohn's disease and places patients at risk for bowel damage. The introduction of novel therapies and the development of new approaches to treatment in rheumatoid arthritis led to better outcomes for patients. Prominent among these is a "treat to target" strategy that is based on regular assessment of disease activity by using objective clinical and biological outcome measures and the subsequent adjustment of treatments. This approach is complementary to the concept of early intervention in high-risk patients. This review evaluates current literature on this topic and proposes a definition for the concept of treating to targets for Crohn's disease.
The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) has proposed treatment ...targets in 2015 for adult patients with inflammatory bowel disease (IBD). We aimed to update the original STRIDE statements for incorporating treatment targets in both adult and pediatric IBD.
Based on a systematic review of the literature and iterative surveys of 89 IOIBD members, recommendations were drafted and modified in 2 surveys and 2 voting rounds. Consensus was reached if ≥75% of participants scored the recommendation as 7 to 10 on a 10-point rating scale.
In the systematic review, 11,278 manuscripts were screened, of which 435 were included. The first IOIBD survey identified the following targets as most important: clinical response and remission, endoscopic healing, and normalization of C-reactive protein/erythrocyte sedimentation rate and calprotectin. Fifteen recommendations were identified, of which 13 were endorsed. STRIDE-II confirmed STRIDE-I long-term targets of clinical remission and endoscopic healing and added absence of disability, restoration of quality of life, and normal growth in children. Symptomatic relief and normalization of serum and fecal markers have been determined as short-term targets. Transmural healing in Crohn’s disease and histological healing in ulcerative colitis are not formal targets but should be assessed as measures of the remission depth.
STRIDE-II encompasses evidence- and consensus-based recommendations for treat-to-target strategies in adults and children with IBD. This frameworkshould be adapted to individual patients and local resources to improve outcomes.
Summary
Background
The gut microbiota plays an important role in the pathogenesis of several gastrointestinal diseases. Its composition and function are shaped by host‐microbiota and intra‐microbiota ...interactions. Bacteriophages (phages) are viruses that target bacteria and have the potential to modulate bacterial communities.
Aims
To summarise phage biology and the clinical applications of phages in gastroenterology
Methods
PubMed was searched to identify relevant studies.
Results
Phages induce bacterial cell lysis, integration of viral DNA into the bacteria and/or coexistence in a stable equilibrium. Bacteria and phages have co‐evolved and their dynamic interactions are yet to be fully understood. The increasing need to modulate microbial communities (e.g., gut microbiota, multidrug‐resistant bacteria) has been a strong stimulus for research in phages as an antibacterial therapy. In gastroenterology, phage therapy has been mainly studied in infectious diseases such as cholera. However, it is currently being explored in several other circumstances such as treating Clostridioides difficile colitis, targeting adherent‐invasive Escherichia coli in Crohn's disease or eradicating Fusobacterium nucleatum in colorectal cancer. Overall, phage therapy has a favourable and acceptable safety profile. Presently, trials with phage therapy are ongoing in Crohn's disease.
Conclusions
Phage therapy is a promising therapeutic tool against pathogenic bacteria in the fields of infectious diseases and gastroenterology. Randomised, placebo‐controlled trials with phage therapy for gastroenterological diseases are ongoing.
Biomarkers of intestinal inflammation, such as faecal calprotectin and C-reactive protein, have been recommended for monitoring patients with Crohn's disease, but whether their use in treatment ...decisions improves outcomes is unknown. We aimed to compare endoscopic and clinical outcomes in patients with moderate to severe Crohn's disease who were managed with a tight control algorithm, using clinical symptoms and biomarkers, versus patients managed with a clinical management algorithm.
CALM was an open-label, randomised, controlled phase 3 study, done in 22 countries at 74 hospitals and outpatient centres, which evaluated adult patients (aged 18–75 years) with active endoscopic Crohn's disease (Crohn's Disease Endoscopic Index of Severity CDEIS >6; sum of CDEIS subscores of >6 in one or more segments with ulcers), a Crohn's Disease Activity Index (CDAI) of 150–450 depending on dose of prednisone at baseline, and no previous use of immunomodulators or biologics. Patients were randomly assigned at a 1:1 ratio to tight control or clinical management groups, stratified by smoking status (yes or no), weight (<70 kg or ≥70 kg), and disease duration (≤2 years or >2 years) after 8 weeks of prednisone induction therapy, or earlier if they had active disease. In both groups, treatment was escalated in a stepwise manner, from no treatment, to adalimumab induction followed by adalimumab every other week, adalimumab every week, and lastly to both weekly adalimumab and daily azathioprine. This escalation was based on meeting treatment failure criteria, which differed between groups (tight control group before and after random assignment: faecal calprotectin ≥250 μg/g, C-reactive protein ≥5mg/L, CDAI ≥150, or prednisone use in the previous week; clinical management group before random assignment: CDAI decrease of <70 points compared with baseline or CDAI >200; clinical management group after random assignment: CDAI decrease of <100 points compared with baseline or CDAI ≥200, or prednisone use in the previous week). De-escalation was possible for patients receiving weekly adalimumab and azathioprine or weekly adalimumab alone if failure criteria were not met. The primary endpoint was mucosal healing (CDEIS <4) with absence of deep ulcers 48 weeks after randomisation. Primary and safety analyses were done in the intention-to-treat population. This trial has been completed, and is registered with ClinicalTrials.gov, number NCT01235689.
Between Feb 11, 2011, and Nov 3, 2016, 244 patients (mean disease duration: clinical management group, 0·9 years SD 1·7; tight control group, 1·0 year 2·3) were randomly assigned to monitoring groups (n=122 per group). 29 (24%) patients in the clinical management group and 32 (26%) patients in the tight control group discontinued the study, mostly because of adverse events. A significantly higher proportion of patients in the tight control group achieved the primary endpoint at week 48 (56 46% of 122 patients) than in the clinical management group (37 30% of 122 patients), with a Cochran–Mantel–Haenszel test-adjusted risk difference of 16·1% (95% CI 3·9–28·3; p=0·010). 105 (86%) of 122 patients in the tight control group and 100 (82%) of 122 patients in the clinical management group reported treatment-emergent adverse events; no treatment-related deaths occurred. The most common adverse events were nausea (21 17% of 122 patients), nasopharyngitis (18 15%), and headache (18 15%) in the tight control group, and worsening Crohn's disease (35 29% of 122 patients), arthralgia (19 16%), and nasopharyngitis (18 15%) in the clinical management group.
CALM is the first study to show that timely escalation with an anti-tumour necrosis factor therapy on the basis of clinical symptoms combined with biomarkers in patients with early Crohn's disease results in better clinical and endoscopic outcomes than symptom-driven decisions alone. Future studies should assess the effects of such a strategy on long-term outcomes such as bowel damage, surgeries, hospital admissions, and disability.
AbbVie.
Strategies for management of inflammatory bowel diseases are shifting from simple control of symptoms toward full control of these diseases (clinical and endoscopic remission), with the final aim of ...blocking their progression and preventing bowel damage and disability. New goals have been proposed for treatment, such as treat to target and tight control based on therapeutic monitoring and early intervention. For patients who achieve clinical remission, there is often interest in discontinuation of therapy due to safety or economic concerns. We review the evidence supporting these emerging paradigms, the reasons that early effective treatment can alter progression of inflammatory bowel diseases, the importance of examining objective signs of inflammation, and the safety of reducing treatment dosage. We also discuss recent findings regarding personalization of care, including factors that predict patient outcomes and response to therapies, as well as preventative strategies.
Summary Background Reports of an increased risk of lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease are controversial. We assessed this risk in a ...prospective observational cohort study. Methods 19 486 patients with inflammatory bowel disease, of whom 11 759 (60·3%) had Crohn's disease and 7727 (39·7%) had ulcerative colitis or unclassified inflammatory bowel disease, were enrolled in a nationwide French cohort by 680 gastroenterologists, who reported details of immunosuppressive therapy during the observation period, cases of cancer, and deaths. The risk of lymphoproliferative disorder was assessed according to thiopurine exposure. Median follow-up was 35 months (IQR 29–40). Findings At baseline, 5867 (30·1%) of patients were receiving, 2809 (14·4%) had discontinued, and 10 810 (55·5%) had never received thiopurines. 23 new cases of lymphoproliferative disorder were diagnosed, consisting of one case of Hodgkin's lymphoma and 22 cases of non-Hodgkin lymphoproliferative disorder. The incidence rates of lymphoproliferative disorder were 0·90 per 1000 (95% CI 0·50–1·49) patient-years in those receiving, 0·20/1000 (0·02–0·72) patient-years in those who had discontinued, and 0·26/1000 (0·10–0·57) patient-years in those who had never received thiopurines (p=0·0054). The multivariate-adjusted hazard ratio of lymphoproliferative disorder between patients receiving thiopurines and those who had never received the drugs was 5·28 (2·01–13·9, p=0·0007). Most cases associated with thiopurine exposure matched the pathological range of post-transplant disease. Interpretation Patients receiving thiopurines for inflammatory bowel disease have an increased risk of developing lymphoproliferative disorders. Funding Programme Hospitalier de Recherche Clinique National ( AOM05157 ), Association François Aupetit, Délégation Inter-régionale de la Recherche clinique Ile de France-Assistance Publique Hôpitaux de Paris (AP-HP), Ligue contre le Cancer, and Fonds de Recherche de la Société Nationale Française de Gastro-entérologie.
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