Vedolizumab for induction and maintenance of remission in Crohn's disease.

BACKGROUND: Vedolizumab blocks inflammatory activity within the gastrointestinal tract. Systematic reviews have demonstrated the efficacy of vedolizumab in ulcerative colitis and inflammatory bowel disease in general. This systematic review and meta-analysis summarises the current evidence of vedolizumab in the induction and maintenance of remission in Crohn's disease. OBJECTIVES: To evaluate the benefits and harms of vedolizumab versus placebo for the induction and maintenance of remission in people with Crohn's disease. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 30 November 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing vedolizumab to placebo for the induction or maintenance of remission in people with Crohn's disease. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. For induction studies, the primary outcome was 1. clinical remission, and secondary outcomes were rates of 2. clinical response, 3. adverse events, 4. serious adverse events, 5. surgery, 6. endoscopic remission and 7. endoscopic response. For maintenance studies, the primary outcome was 1. maintenance of clinical remission, and secondary outcomes were rates of 2. adverse events, 3. serious adverse events, 4. surgery, 5. endoscopic remission and 6. endoscopic response. We used GRADE to assess certainty of evidence. MAIN RESULTS: We analysed induction (4 trials, 1126 participants) and maintenance (3 trials, 894 participants) studies representing people across North America, Europe, Asia and Australasia separately. One maintenance trial administered subcutaneous vedolizumab whilst the other studies used the intravenous form. The mean age ranged between 32.6 and 38.6 years. Vedolizumab was superior to placebo for the induction of clinical remission (71 more per 1000 with clinical remission with vedolizumab; risk ratio (RR) 1.61, 95% confidence interval (CI) 1.20 to 2.17; number needed to treat for an additional beneficial outcome (NNTB) 13; 4 studies; high-certainty evidence) and superior to placebo for inducing clinical response (105 more per 1000 with clinical response with vedolizumab; RR 1.43, 95% CI 1.19 to 1.71; NNTB 8; 4 studies; high-certainty evidence). For the induction phase, vedolizumab may be equivalent to placebo for the development of serious adverse events (9 fewer serious adverse events per 1000 with vedolizumab; RR 0.91, 95% CI 0.62 to 1.33; 4 studies; low-certainty evidence) and probably equivalent to placebo for overall adverse events (6 fewer adverse events per 1000 with vedolizumab; RR 1.01, 95% CI 0.93 to 1.11; 4 studies; moderate-certainty evidence). Vedolizumab was superior to placebo for the maintenance of clinical remission (141 more per 1000 with maintenance of clinical remission with vedolizumab; RR 1.52, 95% CI 1.24 to 1.87; NNTB 7; 3 studies; high-certainty evidence). During the maintenance phase, vedolizumab may be equivalent to placebo for the development of serious adverse events (3 fewer serious adverse events per 1000 with vedolizumab; RR 0.98, 95% CI 0.68 to 1.39; 3 studies; low-certainty evidence) and probably equivalent to placebo for the development of overall adverse events (0 difference in adverse events per 1000; RR 1.00, 95% CI 0.94 to 1.07; 3 studies; moderate-certainty evidence). AUTHORS' CONCLUSIONS: High-certainty data across four induction and three maintenance trials demonstrate that vedolizumab is superior to placebo in the induction and maintenance of remission in Crohn's disease. Overall adverse events are probably similar and serious adverse events may be similar between vedolizumab and placebo during both induction and maintenance phases of treatment. Head-to-head research comparing the efficacy and safety of vedolizumab to other biological therapies is required.

Antibody response to the COVID-19 ChAdOx1nCov-19 and BNT162b vaccines after temporary suspension of DMARD therapy in immune-mediated inflammatory disease (RESCUE).

OBJECTIVE: To assess the antibody response to disease-modifying antirheumatic drug (DMARD) therapy after the first and second dose of the ChAdOx1nCov-19 (AstraZeneca (AZ)) and BNT162b (Pfizer) vaccines in patients with immune-mediated inflammatory disease (IMID) compared with controls and if withholding therapy following the first vaccination dose has any effect on seroconversion and SARS-CoV-2 antibody (Ab) levels. METHODS: A multicentre three-arm randomised controlled trial compared the immunogenicity of the Pfizer and AZ vaccines in adult patients on conventional synthetic (csDMARD), biologic (bDMARD) or targeted synthetic (tsDMARD) therapy for IMID (n=181) with a control group (n=59). Patients were randomised to continue or withhold DMARD therapy for 1-2 weeks post first dose vaccination only. Serum SARS-CoV-2 IgG detection (IgG ≥1.0 U/mL) and titres against the S1/S2 proteins were measured at baseline, 3-4 weeks post first vaccination and 4 weeks post second vaccination. RESULTS: AZ vaccination was given to 47.5%, 41.5% and 52.5% in the continue, withhold and control groups, respectively while Pfizer vaccination was given to 52.5%, 58.5% and 47.5% among the continue, withhold and control groups, respectively. Seroconversion rates following the first dose in the AZ and Pfizer groups were only 27.3% vs 79.2% (p=0.000) and 64.58% vs 100% (p=0.000), respectively in the IMID groups who continued therapy compared with the AZ and Pfizer controls, respectively. Withholding DMARD therapy following the first vaccination dose resulted in higher seroconversion to 67.7% and 84.1% in the AZ and Pfizer groups, respectively. Following the second AZ and Pfizer vaccinations when all DMARDs were continued, despite a slightly lower seroconversion rate (83.7% vs 100%, p=0.000 and 95.9% vs 100%, p=0.413), respectively, the mean SARS-CoV2 IgG Ab titres were not significantly different in the csDMARD and bDMARD groups compared with the controls regardless of hold while it was significantly lower in patients taking tsDMARD (12.88 vs 79.49 U/mL, p=0.000). CONCLUSIONS: Following the first vaccination dose, antibody responses were lower in IMID on DMARD therapy, however the final responses were excellent regardless of hold with the exception of the tsDMARD group where withholding therapy is recommended. At least 2 vaccinations are therefore recommended preferably with an messenger RNA vaccine. TRIAL REGISTRATION NUMBER: ANZCTR: 12621000661875.

Systematic Review: The Impact and Importance of Body Composition in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Alterations in body composition are common in inflammatory bowel disease [IBD] and have been associated with differences in patient outcomes. We sought to consolidate knowledge on the impact and importance of body composition in IBD. METHODS: We performed a systematic search of MEDLINE, EMBASE and conference proceedings by combining two key research themes: inflammatory bowel disease and body composition. RESULTS: Fifty-five studies were included in this review. Thirty-one focused on the impact of IBD on body composition with a total of 2279 patients with a mean age 38.4 years. Of these, 1071 [47%] were male. In total, 1470 [64.5%] patients had Crohn's disease and 809 [35.5%] had ulcerative colitis. Notably, fat mass and fat-free mass were reduced, and higher rates of sarcopaenia were observed in those with active IBD compared with those in clinical remission and healthy controls. Twenty-four additional studies focused on the impact of derangements in body composition on IBD outcomes. Alterations in body composition in IBD are associated with poorer prognoses including higher rates of surgical intervention, post-operative complications and reduced muscle strength. In addition, higher rates of early treatment failure and primary non-response are seen in patients with myopaenia. CONCLUSIONS: Patients with IBD have alterations in body composition parameters in active disease and clinical remission. The impacts of body composition on disease outcome and therapy are broad and require further investigation. The augmentation of body composition parameters in the clinical setting has the potential to improve IBD outcomes in the future.

Interventions to Improve Adherence to Preventive Care in Inflammatory Bowel Disease: A Systematic Review.

BACKGROUND: Preventive health measures reduce treatment and disease-related complications including infections, osteoporosis, and malignancies in patients with inflammatory bowel disease (IBD). Although guidelines and quality measures for IBD care highlight the importance of preventive care, their uptake remains variable. This systematic review evaluates interventions aimed at improving the rates of provision and uptake of preventive health measures, including vaccinations, bone density assessment, skin cancer screening, cervical cancer screening, and smoking cessation counseling. METHODS: We searched PubMed, MEDLINE, EMBASE, and CENTRAL for full text articles published until March 2021. Studies were included if they evaluated interventions to improve the provision or uptake of 1 or more preventive health measures in adult IBD patients and if they reported pre- and postintervention outcomes. RESULTS: In all, 4655 studies were screened, and a total of 17 studies were included, including 1 randomized controlled trial, 1 cluster-controlled trial, and 15 prospective interventional studies. A variety of interventions were effective in improving the rates of adherence to preventive health measures. The most common interventions targeted gastroenterologists, including education, electronic medical records tools, and audit feedback. Other interventions targeted patients, such as education, questionnaires, and offering vaccine administration at clinic visits. Few interventions involved IBD nurses or primary care physicians. CONCLUSIONS: A range of interventions-targeted at gastroenterologists, patients, or both-were effective in improving the provision and uptake of preventive care. Future studies should involve randomized controlled trials evaluating multifaceted interventions that target barriers to adherence and involve IBD nurses and primary care physicians.

Prospective randomised controlled trial of adults with perianal fistulising Crohn's disease and optimised therapeutic infliximab levels: PROACTIVE trial study protocol.

INTRODUCTION: Perianal fistulising Crohn's disease (pfCD) can be somewhat treatment refractory. Higher infliximab trough levels (TLIs) may improve fistula healing rates; however, it remains unclear whether escalating infliximab therapy to meet higher TLI targets using proactive, or routine, therapeutic drug monitoring (TDM) improves outcomes. This randomised controlled trial aimed to assess whether infliximab therapy targeting higher TLIs guided by proactive TDM improves outcomes compared with standard therapy. METHODS AND ANALYSIS: Patients with active pfCD will be randomised 1:1 to either the proactive TDM arm or standard dosing arm and followed up for 54 weeks. Patients in the proactive TDM arm will have infliximab dosing optimised to target higher TLIs. The targets will be TLI ≥ 25 µg/mL at week 2, ≥ 20 µg/mL at week 6 and ≥ 10 µg/mL during maintenance therapy. The primary objective will be fistula healing at week 32. Secondary objectives will include fistula healing, fistula closure, radiological fistula healing, patient-reported outcomes and economic costs up to 54 weeks. Patients in the standard dosing arm will receive conventional infliximab dosing not guided by TLIs (5 mg/kg at weeks 0, 2 and 6, and 5 mg/kg 8 weekly thereafter). Patients aged 18-80 years with pfCD with single or multiple externally draining complex perianal fistulas who are relatively naïve to infliximab treatment will be included. Patients with diverting ileostomies or colostomies and pregnant or breast feeding will be excluded. Fifty-eight patients per arm will be required to detect a 25% difference in the primary outcome measure, with 138 patients needed to account for an estimated 6.1% primary non-response rate and 10% dropout rate. ETHICS AND DISSEMINATION: Results will be presented in peer-reviewed journals and international conferences. Ethics approval has been granted by the South Western Sydney Local Health District Human Research Ethics Committee in Australia. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12621000023853); Pre-results.

Long-term outcomes of perianal fistulizing Crohn's disease in the biologic era.

BACKGROUND AND AIM: While the advent of biologic therapy has led to improved outcomes in perianal fistulizing Crohn's disease (pfCD), loss of response is common. Previous studies suggest that patients who achieve radiological healing (with healing of underlying tracts on magnetic resonance imaging [MRI]) have a longer duration of response. The aim of this study was to characterize MRI outcomes of pfCD at a specialist inflammatory bowel disease (IBD) unit and compare the long-term clinical outcomes between patients achieving MRI and clinical healing. METHODS: A retrospective analysis of perianal fistulizing Crohn's patients treated at one specialist IBD unit was performed. Records were reviewed for patient demographics, disease history, clinical assessments, investigation results, and disease flares. Clinical remission was defined as closure of all baseline fistula openings. Radiological healing was defined as the absence of any T2-hyperintense sinuses, tracts, or collections. The primary end-point was rate of MRI healing. The secondary outcome was defined as flare-free period (time between clinical or radiological healing and patients' first signs/symptoms requiring therapy escalation). RESULTS: A total of 93 patients were included, with a median follow-up of 4.8 years (interquartile range, 2.4-6 years). Of 44 patients, 22 (50%) achieved clinical remission, while 15 of 93 (16%) achieved radiological healing. Of 22 patients, 10 (45%) with clinical remission had a subsequent disease flare (median time of 7 months) compared with 3 of 15 (20%) patients with MRI healing (median time of 3.6 years). Radiological healing was associated with a significantly longer flare-free period (P = 0.01). CONCLUSION: Radiological healing occurs less commonly but represents a deeper form of healing, associated with improved long-term clinical outcomes.

Cumulative burden of inflammation predicts colorectal neoplasia risk in ulcerative colitis: a large single-centre study.

OBJECTIVE: Ulcerative colitis (UC) is a dynamic disease with its severity continuously changing over time. We hypothesised that the risk of colorectal neoplasia (CRN) in UC closely follows an actuarial accumulative inflammatory burden, which is inadequately represented by current risk stratification strategies. DESIGN: This was a retrospective single-centre study. Patients with extensive UC who were under colonoscopic surveillance between 2003 and 2012 were studied. Each surveillance episode was scored for a severity of microscopic inflammation (0=no activity; 1=mild; 2=moderate; 3=severe activity). The cumulative inflammatory burden (CIB) was defined as sum of: average score between each pair of surveillance episodes multiplied by the surveillance interval in years. Potential predictors were correlated with CRN outcome using time-dependent Cox regression. RESULTS: A total of 987 patients were followed for a median of 13 years (IQR, 9-18), 97 (9.8%) of whom developed CRN. Multivariate analysis showed that the CIB was significantly associated with CRN development (HR, 2.1 per 10-unit increase in CIB (equivalent of 10, 5 or 3.3 years of continuous mild, moderate or severe active microscopic inflammation); 95% CI 1.4 to 3.0; P<0.001). Reflecting this, while inflammation severity based on the most recent colonoscopy alone was not significant (HR, 0.9 per-1-unit increase in severity; 95% CI 0.7 to 1.2; P=0.5), a mean severity score calculated from all colonoscopies performed in preceding 5 years was significantly associated with CRN risk (HR, 2.2 per-1-unit increase; 95% CI 1.6 to 3.1; P<0.001). CONCLUSION: The risk of CRN in UC is significantly associated with accumulative inflammatory burden. An accurate CRN risk stratification should involve assessment of multiple surveillance episodes to take this into account.

Efficacy of Endoscopic Dilation of Gastroduodenal Crohn's Disease Strictures: A Systematic Review and Meta-Analysis of Individual Patient Data.

BACKGROUND & AIMS: Little is known about the effects of endoscopic balloon dilation (EBD) for strictures of the upper gastrointestinal (UGI) tract in patients with Crohn's disease (CD). We performed a pooled analysis of the efficacy and safety of EBD for UGI CD-associated strictures. METHODS: We searched Embase, Medline, and the Cochrane library, as well as bibliographies of relevant articles, for cohort studies of adults with CD and strictures of the stomach or duodenum (up to the ligament of Treitz) who underwent EBD through December 2016. We obtained data from 7 international referral centers on 94 patients who underwent 141 EBDs. We performed a patient-level meta-analysis of data from published and unpublished cohort studies to determine mechanical and clinical success. We performed a time-to-event analysis to assess symptom recurrence and need for redilation or surgery. The patients analyzed had strictures of the duodenum (n = 107), stomach (n = 30), or spanning both (n = 4). RESULTS: The rate of technical success for EBD was 100%, with 87% short-term clinical efficacy; major complications arose from 2.9% of all procedures. During a median follow-up period of 23.1 months, 70.5% of patients had a recurrence of symptoms, 59.6% required redilation, and 30.8% required surgical intervention. Patients whose disease was located in the small bowel had a higher risk for symptom recurrence (hazard ratio [HR], 2.1; P = .003). Asian race (HR, 2.8; P < .001) and location of disease in the small bowel (HR, 1.9; P = .004) increased the need for redilation. Prestenotic dilation was a risk factor for needing surgery earlier (HR, 1.9; P = .001). CONCLUSIONS: In a meta-analysis, we found EBD for CD-associated strictures of the UGI to be an effective alternative to surgery, with a high rate of short-term technical and clinical success, moderate long-term efficacy, and an acceptable rate of complications.

Quantitative phase microscopy for evaluation of intestinal inflammation and wound healing utilizing label-free biophysical markers.

Inflammatory bowel diseases (IBD) are inflammatory disorders of the gastrointestinal tract characterized by a chronic relapsing disease course. As uncontrolled intestinal inflammation can result in severe disease complications, recent treatment targets of IBD evolved toward seeking the absence of mucosal and histological inflammation. However, this approach requires adequate histological evaluation of IBD disease activity. The diagnostic challenge of histological examination of intestinal inflammation is documented by the multitude of proposed histological scoring systems. In this context, we review quantitative phase imaging (QPI) techniques such as digital holographic microscopy (DHM) for characterizing intestinal inflammation. DHM determines optical path-length delays in a stain-free manner, thereby providing the tissue refractive index as a biophysical marker that directly correlates to tissue density. Recently, DHM has been successfully applied in cell biology, cancer cell research and infectious-induced cellular alterations. We summarized the capabilities of DHM and related QPI techniques to assess the severity of intestinal inflammation in experimental colitis as well as in colonic samples from human IBD patients. Moreover, we illustrate major advantages of DHM facilitated multimodal evaluation of epithelial wound healing processes as assessed by physical parameters like cell volume, density, thickness and dry mass in vitro. Furthermore, potential limitations of DHM and future utilities of QPI are discussed. In conclusion, DHM represents a promising, easy-to-use quantitative tool to provide accurate and objective assessment of intestinal inflammation and may pave the way towards automated label-free digital pathology and related in vitro cell culture analysis in future.

Endoscopic Dilatation of Crohn's Anastomotic Strictures is Effective in the Long Term, and Escalation of Medical Therapy Improves Outcomes in the Biologic Era.

BACKGROUND AND AIMS: To investigate the long-term efficacy of endoscopic dilatation of Crohn's anastomotic strictures and to identify risk and protective factors associated with the need for repeat dilatation or surgery. METHODS: A total of 54 patients who had endoscopic balloon dilatations for anastomotic Crohn's strictures between 2004 and 2009, with follow-up until June 2014, were identified from a single tertiary center. The primary end points were repeat dilatation or surgical resection, and the impact of radiology, medical therapy, and endoscopic data on these outcomes was analysed with Cox proportional hazards analysis. RESULTS: A total of 151 dilatations were performed on patients with a median age of 52 years [interquartile range (IQR), 46-62 years]. The median duration from the first to the second dilatation was 6 years (IQR, 5-7 years). The median disease duration was 28 years (IQR, 19-32 years). At endoscopy, disease activity was reported in 50/54 (92%) cases, with a median Rutgeerts grading of i2 (range, i0-i4). A median of two (IQR 1-9) dilatations was required, with a time to repeat dilatation of 23 months (IQR 7.2-56.9). Escalation of medical therapy was adopted in 22/54 patients (41% of the study population). On multivariate analysis, only combination therapy (anti-TNFα and immunomodulator) was significantly associated with the (decreased) need for repeated dilatation [hazard ratio (HR) 0.23; 95% CI, 0.07-0.67; p = 0.01]. Anastomotic resections were performed in 10 (18%) patients, with a Rutgeerts score of i4 at initial endoscopic balloon dilatation being associated with this outcome (HR 4.55; 95% CI 1.08-19.29; p = 0.04) on multivariate analysis. CONCLUSION: Endoscopic balloon dilatation of Crohn's anastomotic strictures is safe and effective in the long term. We demonstrate that active disease predicts for future surgery, while escalation of medical therapy may decrease the need for repeat dilatation.