The risk of colectomy and colorectal cancer after appendectomy in patients with ulcerative colitis:a systematic review and meta-analysis

Background: Appendectomy decreases the risk of developing ulcerative colitis [UC], and is suggested to have a beneficial effect on the clinical course of established UC. However, recent studies showed no significantly decreased colectomy rate, and moreover an apparently increased risk of colorectal cancer [CRC]. We aimed to investigate the suggested correlation in a meta-analysis and to analyse possible confounding factors. Methods: A systematic review and meta-analysis were performed using MEDLINE, EMBASE, and the Cochrane Library. Data from studies describing the influence of appendectomy on colectomy and CRC were extracted from published reports. Exclusion criteria were patients aged <18 years, non-UC, and animal studies. Results: From 891 studies, 13 studies evaluating 73 323 UC patients [appendectomy n = 2859] were included. All studies, except one, were rated as poor quality. Overall, colectomy rate in appendectomised and non-appendectomised patients was not significantly different (odds ratio [OR] 1.25, 95% confidence interval [CI] 0.88-1.77, I2 = 53%). The proportion of colectomies undertaken for CRC or high-grade dysplasia [HGD] was significantly higher after appendectomy [OR 2.85, 95% CI 1.40-5.78, I2 = 32%], with 50% of the colectomies indicated for CRC/HGD compared with 9.4% in non-appendectomised patients. Possible additional confounding factors were a longer UC disease duration, less medication use, and a higher prevalence of primary sclerosing cholangitis [PSC] in appendectomised patients. Conclusions: Appendectomy in established UC is associated with apparently higher rates of subsequent CRC/HGD, but this appears to be due to inequalities in at-risk exposure between groups, presumably secondary to positive clinical effects of appendectomy on disease symptoms. This finding emphasises the importance of regular endoscopic surveillance in this patient group

Central-line-associated bloodstream infection burden among Dutch neonatal intensive care units

Background: The establishment of an epidemiological overview provides valuable insights needed for the (future) dissemination of infection-prevention initiatives. Aim: To describe the nationwide epidemiology of central-line-associated bloodstream infections (CLABSI) among Dutch Neonatal Intensive Care Units (NICUs). Methods: Data from 2935 neonates born at &lt;32 weeks' gestation and/or with a birth weight &lt;1500 g admitted to all nine Dutch NICUs over a two-year surveillance period (2019–2020) were analysed. Variations in baseline characteristics, CLABSI incidence per 1000 central-line days, pathogen distribution and CLABSI care bundles were evaluated. Multi-variable logistic mixed-modelling was used to identify significant predictors for CLABSI. Results:A total of 1699 (58%) neonates received a central line, in which 160 CLABSI episodes were recorded. Coagulase-negative staphylococci were the most common infecting organisms of all CLABSI episodes (N=100, 63%). An almost six-fold difference in the CLABSI incidence between participating units was found (2.91–16.14 per 1000 line-days). Logistic mixed-modelling revealed longer central line dwell-time (adjusted odds ratio (aOR):1.08, P&lt;0.001), umbilical lines (aOR:1.85, P=0.03) and single rooms (aOR:3.63, P=0.02) to be significant predictors of CLABSI. Variations in bundle elements included intravenous tubing care and antibiotic prophylaxis. Conclusions: CLABSI remains a common problem in preterm infants in The Netherlands, with substantial variation in incidence between centres. Being the largest collection of data on the burden of neonatal CLABSI in The Netherlands, this epidemiological overview provides a solid foundation for the development of a collaborative platform for continuous surveillance, ideally leading to refinement of national evidence-based guidelines. Future efforts should focus on ensuring availability and extraction of routine patient data in aggregated formats.</p

Innovative approaches to biologic development on the trail of CT-P13: biosimilars, value-added medicines, and biobetters.

The biosimilar concept is now well established. Clinical data accumulated pre- and post-approval have supported biosimilar uptake, in turn stimulating competition in the biologics market and increasing patient access to biologics. Following technological advances, other innovative biologics, such as "biobetters" or "value-added medicines," are now reaching the market. These innovative biologics differ from the reference product by offering additional clinical or non-clinical benefits. We discuss these innovative biologics with reference to CT-P13, initially available as an intravenous (IV) biosimilar of reference infliximab. A subcutaneous (SC) formulation, CT-P13 SC, has now been developed. Relative to CT-P13 IV, CT-P13 SC offers clinical benefits in terms of pharmacokinetics, with comparable efficacy, safety, and immunogenicity, as well as increased convenience for patients and reduced demands on healthcare system resources. As was once the case for biosimilars, nomenclature and regulatory pathways for innovative biologics require clarification to support their uptake and ultimately benefit patients

Effect of liver transplantation on inflammatory bowel disease in patients with primary sclerosing cholangitis

This report investigates the influence of liver transplantation and concomitant immunosuppression on the course of progression of inflammatory bowel disease (IBD) and discusses statistical methodology appropriate for such settings. The data on 303 patients who underwent liver transplantation for primary sclerosing cholangitis (PSC) were analyzed using person-time analysis and Cox regression, with the duration of IBD as the time variable and transplantation as a segmented time-dependent covariate, to take into account both posttransplant and pretransplant history of IBD. The need for colectomy and appearance of colorectal cancer were taken as outcome measures. The only significant risk factor in the multivariate model for colectomy was transplantation itself, which increased the risk of colectomy due to intractable disease (Wald statistic; P =. 001). None of the variables available for analysis were found to influence the risk of colon cancer significantly. Graphs showing the dependence of the instantaneous risk of cancer on the time from onset of IBD and its independence from the latter in the case of colectomy are presented. The use of a unique statistical methodology described for the first time in this setting led us to the somewhat surprising conclusion that transplantation and concomitant use of immunosuppression accelerate the progression of IBD. At the same time, transplantation does not affect the incidence of colorectal cancer. These results confirm the findings of some recent studies and can potentially shed new light on the disease pathogenesis

Patients' perspectives on a drug safety monitoring system for immune-mediated inflammatory diseases based on patient-reported outcomes

Patient-reported outcomes (PROs) on adverse drug reactions (ADRs) are increasingly used in cohort event monitoring (CEM) to obtain a better understanding of patients’ real-world experience with drugs. Despite the leading role for patients, little is known about their perspectives on CEM systems. In a cross-sectional open survey following the rationale of the Technology Acceptance Model, we aimed to obtain insight in patients’ perspectives on the perceived usefulness, ease of use and attitude toward using a PRO-based drug safety monitoring system for ADRs attributed to biologics. Patients considered structural reporting of ADRs in web-based questionnaires as useful and not burdensome. It was preferred to link the questionnaire frequency to regular hospital consultations or the biologic administration schedule. Various respondents were interested in sharing questionnaires with their medical specialist (49.0%) or pharmacist (34.2%), and suggested to minimize the questionnaire frequency in case of an unaltered situation or absence of ADRs. Patients’ perspectives should be considered in the setup of PRO-based CEM studies, as this contributes to data quality and patient centeredness. Since incorporation of patients’ perspectives in CEM studies is indispensable, a delicate balance should be found between user-friendliness and study aims.</p

Tofacitinib as induction and maintenance therapy for ulcerative colitis

Background: Tofacitinib, an oral, small-molecule Janus kinase inhibitor, was shown to have potential efficacy as induction therapy for ulcerative colitis in a phase 2 trial. We further evaluated the efficacy of tofacitinib as induction and maintenance therapy. METHODS: We conducted three phase 3, randomized, double-blind, placebo-controlled trials of tofacitinib therapy in adults with ulcerative colitis. In the OCTAVE Induction 1 and 2 trials, 598 and 541 patients, respectively, who had moderately to severely active ulcerative colitis despite previous conventional therapy or therapy with a tumor necrosis factor antagonist were randomly assigned to receive induction therapy with tofacitinib (10 mg twice daily) or placebo for 8 weeks. The primary end point was remission at 8 weeks. In the OCTAVE Sustain trial, 593 patients who had a clinical response to induction therapy were randomly assigned to receive maintenance therapy with tofacitinib (either 5 mg or 10 mg twice daily) or placebo for 52 weeks. The primary end point was remission at 52 weeks. RESULTS: In the OCTAVE Induction 1 trial, remission at 8 weeks occurred in 18.5% of the patients in the tofacitinib group versus 8.2% in the placebo group (P=0.007); in the OCTAVE Induction 2 trial, remission occurred in 16.6% versus 3.6% (P<0.001). In the OCTAVE Sustain trial, remission at 52 weeks occurred in 34.3% of the patients in the 5-mg tofacitinib group and 40.6% in the 10-mg tofacitinib group versus 11.1% in the placebo group (P<0.001 for both comparisons with placebo). In the OCTAVE Induction 1 and 2 trials, the rates of overall infection and serious infection were higher with tofacitinib than with placebo. In the OCTAVE Sustain trial, the rate of serious infection was similar across the three treatment groups, and the rates of overall infection and herpes zoster infection were higher with tofacitinib than with placebo. Across all three trials, adjudicated nonmelanoma skin cancer occurred in five patients who received tofacitinib and in one who received placebo, and adjudicated cardiovascular events occurred in five who received tofacitinib and in none who received placebo; as compared with placebo, tofacitinib was associated with increased lipid levels. CONCLUSIONS: In patients with moderately to severely active ulcerative colitis, tofacitinib was more effective as induction and maintenance therapy than placebo. (Funded by Pfizer; OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain ClinicalTrials.gov numbers, NCT01465763 , NCT01458951 , and NCT01458574 , respectively.

Infliximab Induces Clonal Expansion of γδ-T Cells in Crohn's Disease: A Predictor of Lymphoma Risk?

BACKGROUND: Concominant with the widespread use of combined immunotherapy in the management of Crohn's disease (CD), the incidence of hepato-splenic gamma-delta (γδ)-T cell lymphoma has increased sharply in CD patients. Malignant transformation of lymphocytes is believed to be a multistep process resulting in the selection of malignant γδ-T cell clones. We hypothesised that repeated infusion of anti-TNF-α agents may induce clonal selection and that concurrent treatment with immunomodulators further predisposes patients to γδ-T cell expansion. METHODOLOGY/PRINCIPAL FINDINGS: We investigated dynamic changes in the γδ-T cells of patient with CD following treatment with infliximab (Remicade®; n=20) or adalimumab (Humira®; n=26) using flow cytometry. In patients with a high γδ-T cell level, the γδ-T cells were assessed for clonality. Of these 46 CD patients, 35 had a γδ-T cells level (mean 1.6%) comparable to healthy individuals (mean 2.2%), and 11 CD patients (24%) exhibited an increased level of γδ-T cells (5-15%). In the 18 patients also receiving thiopurines or methotrexate, the average baseline γδ-T cell level was 4.4%. In three male CD patients with a high baseline value, the γδ-T cell population increased dramatically following infliximab therapy. A fourth male patient also on infliximab monotherapy presented with 20% γδ-T cells, which increased to 25% shortly after treatment and was 36% between infusions. Clonality studies revealed an oligoclonal γδ-T cell pattern with dominant γδ-T cell clones. In support of our clinical findings, in vitro experiments showed a dose-dependent proliferative effect of anti-TNF-α agents on γδ-T cells. CONCLUSION/SIGNIFICANCE: CD patients treated with immunomodulators had constitutively high levels of γδ-T cells. Infliximab exacerbated clonal γδ-T cell expansion in vivo and induced γδ-T cell proliferation in vitro. Overall, young, male CD patients with high baseline γδ-T cell levels may be at an increased risk of developing malignant γδ-T cell lymphomas following treatment with anti-TNF-α agents

Outcome measurement in clinical trials for Ulcerative Colitis: towards standardisation

Clinical trials on novel drug therapies require clear criteria for patient selection and agreed definitions of disease remission. This principle has been successfully applied in the field of rheumatology where agreed disease scoring systems have allowed multi-centre collaborations and facilitated audit across treatment centres. Unfortunately in ulcerative colitis this consensus is lacking. Thirteen scoring systems have been developed but none have been properly validated. Most trials choose different endpoints and activity indices, making comparison of results from different trials extremely difficult. International consensus on endoscopic, clinical and histological scoring systems is essential as these are the key components used to determine entry criteria and outcome measurements in clinical trials on ulcerative colitis. With multiple new therapies under development, there is a pressing need for consensus to be reached

The effects of thiopurine therapy on health-related quality of life in Inflammatory Bowel Disease patients

<p>Abstract</p> <p>Background</p> <p>The effect of thiopurine immunomodulators on health-related quality of life (HRQoL) in patients with inflammatory bowel disease (IBD) has been controversial. The aims were to evaluate the HRQoL in patients with IBD treated with thiopurines and assess the short- and long-term impacts of the treatment on HRQoL.</p> <p>Methods</p> <p>Ninety-two consecutive patients who started treatment with thiopurines were prospectively included. Evaluation of HRQoL was performed at months 0, 6, and 12 using two questionnaires, the Short-Form Health Survey (SF-36) and the Inflammatory Bowel Disease Questionnaire (IBDQ).</p> <p>Results</p> <p>Baseline score of IBDQ was 4,6, range (2,31-6,84), with an impairment of the five dimensions of HRQoL compared with inactive patients. Results obtained in 8 dimensions of SF-36 showed worse HRQoL than Spanish general population. At 6 months patients had a significant improvement in overall IBDQ score -5,8 (1,58 -6,97)- and also in all IBDQ dimensions. All the 8 dimensions of SF-36 obtained a significant improvement. At twelve months score of IBDQ was 6,1, range (2,7-6,98), with improvement in all dimensions compared with baseline and 6 months. SF-36 showed a similar significant improvement in all subscales.</p> <p>Conclusions</p> <p>Thiopurine immunomodulators alone or with other treatments have a positive and long lasting impact on HRQoL of IBD patients.</p