Summary
Background
Risk benefit strategies in managing inflammatory bowel diseases (IBD) are dependent upon understanding the risks of uncontrolled inflammation vs those of treatments. Malignancy and ...mortality in IBD have been associated with disease‐related inflammation and immune suppression, but data are limited due to their rare occurrence.
Aim
To identify and describe the most common causes of mortality, types of cancer and previous or current therapy among children and young adults with paediatric‐onset IBD.
Methods
Information on paediatric‐onset IBD patients diagnosed with malignancy or mortality was prospectively collected via a survey in 25 countries over a 42‐month period. Patients were included if death or malignancy occurred after IBD diagnosis but before the age of 26 years.
Results
In total, 60 patients were identified including 43 malignancies and 26 fatal cases (9 due to cancer). Main causes of fatality were malignancies (n = 9), IBD or IBD‐therapy related nonmalignant causes (n = 10; including 5 infections), and suicides (n = 3). Three cases, all fatal, of hepatosplenic T‐cell lymphoma were identified, all were biologic‐naïve but thiopurine‐exposed. No other haematological malignancies were fatal. The 6 other fatal cancer cases included 3 colorectal adenocarcinomas and 3 cholangiocarcinomas (CCAs). Primary sclerosing cholangitis (PSC) was present in 5 (56%) fatal cancers (1 colorectal carcinoma, 3 CCAs and 1 hepatosplenic T‐cell lymphoma).
Conclusions
We report the largest number of paediatric‐onset IBD patients with cancer and/or fatal outcomes to date. Malignancies followed by infections were the major causes of mortality. We identified PSC as a significant risk factor for cancer‐associated mortality. Disease‐related adenocarcinomas were a commoner cause of death than lymphomas.
While the opportunities of ML and AI in healthcare are promising, the growth of complex data-driven prediction models requires careful quality and applicability assessment before they are applied and ...disseminated in daily practice. This scoping review aimed to identify actionable guidance for those closely involved in AI-based prediction model (AIPM) development, evaluation and implementation including software engineers, data scientists, and healthcare professionals and to identify potential gaps in this guidance. We performed a scoping review of the relevant literature providing guidance or quality criteria regarding the development, evaluation, and implementation of AIPMs using a comprehensive multi-stage screening strategy. PubMed, Web of Science, and the ACM Digital Library were searched, and AI experts were consulted. Topics were extracted from the identified literature and summarized across the six phases at the core of this review: (1) data preparation, (2) AIPM development, (3) AIPM validation, (4) software development, (5) AIPM impact assessment, and (6) AIPM implementation into daily healthcare practice. From 2683 unique hits, 72 relevant guidance documents were identified. Substantial guidance was found for data preparation, AIPM development and AIPM validation (phases 1-3), while later phases clearly have received less attention (software development, impact assessment and implementation) in the scientific literature. The six phases of the AIPM development, evaluation and implementation cycle provide a framework for responsible introduction of AI-based prediction models in healthcare. Additional domain and technology specific research may be necessary and more practical experience with implementing AIPMs is needed to support further guidance.
In newly diagnosed paediatric patients with moderate-to-severe Crohn's disease (CD), infliximab (IFX) is initiated once exclusive enteral nutrition (EEN), corticosteroid and immunomodulator therapies ...have failed. We aimed to investigate whether starting first-line IFX (FL-IFX) is more effective to achieve and maintain remission than conventional treatment.
In this multicentre open-label randomised controlled trial, untreated patients with a new diagnosis of CD (3-17 years old, weighted Paediatric CD Activity Index score (wPCDAI) >40) were assigned to groups that received five infusions of 5 mg/kg IFX at weeks 0, 2, 6, 14 and 22 (FL-IFX), or EEN or oral prednisolone (1 mg/kg, maximum 40 mg) (conventional). The primary outcome was clinical remission on azathioprine, defined as a wPCDAI <12.5 at week 52, without need for treatment escalation, using intention-to-treat analysis.
100 patients were included, 50 in the FL-IFX group and 50 in the conventional group. Four patients did not receive treatment as per protocol. At week 10, a higher proportion of patients in the FL-IFX group than in the conventional group achieved clinical (59% vs 34%, respectively, p=0.021) and endoscopic remission (59% vs 17%, respectively, p=0.001). At week 52, the proportion of patients in clinical remission was not significantly different (p=0.421). However, 19/46 (41%) patients in the FL-IFX group were in clinical remission on azathioprine monotherapy without need for treatment escalation vs 7/48 (15%) in the conventional group (p=0.004).
FL-IFX was superior to conventional treatment in achieving short-term clinical and endoscopic remission, and had greater likelihood of maintaining clinical remission at week 52 on azathioprine monotherapy.
ClinicalTrials.gov Registry (NCT02517684).
Asthma and chronic obstructive pulmonary disease (COPD) affect millions of people worldwide. While medication can control and improve disease symptoms, incorrect use of medication is a common ...problem. The eHealth intervention SARA (Service Apothecary Respiratory Advice) aims to improve participants' correct use of inhalation medication by providing information and as-needed tailored follow-up support by a pharmacist.
The primary aim of this study was to investigate the effect of SARA on exacerbation rates in participants with asthma and COPD. Secondary aims were to investigate its effects in terms of adherence to maintenance medication and antimycotic treatment.
In this nonrandomized pre-post study, medication dispensing data from 382 Dutch community pharmacies were included. Exacerbation rates were assessed with dispensed short-course oral corticosteroids. Medication adherence between new and chronic users was assessed by calculating the proportion of days covered from dispensed inhalation maintenance medication. Antimycotic treatment was investigated from dispensed oral antimycotics in participants who were also dispensed inhaled corticosteroids (ICS). Outcomes were assessed 1 year before and 1 year after implementation of SARA and were compared between SARA participants and control participants. More specifically, for exacerbation rates and medication adherence, a difference score was calculated (ie, 1 year after SARA minus 1 year before SARA) and was subsequently compared between the study groups with independent-samples t tests. For antimycotics, the relative number of participants who were dispensed antimycotics was calculated and subsequently analyzed with a mixed-effects logistic regression.
The study population comprised 9452 participants, of whom 2400 (25.39%) were SARA participants. The mean age of the population was 60.8 (15.0) years, and approximately two-thirds (n=5677, 60.06%) were female. The results showed an increase in mean exacerbation rates over time for both study groups (SARA: 0.05; control: 0.15). However, this increase in exacerbation rates was significantly lower for SARA participants (t
=3.10, 95% CI 0.04-0.16; P=.002; Cohen d=0.06). Chronic users of inhalation medication in both study groups showed an increase in mean medication adherence over time (SARA: 6.73; control: 4.48); however, this increase was significantly higher for SARA participants (t
=-2.74, 95% CI -3.86 to -0.84; P=.01; Cohen d=-0.07). Among new users of inhalation medication, results showed no significant difference in medication adherence between SARA and control participants in the year after implementation of SARA (t
=-1.85, 95% CI -5.60 to 0.16; P=.06; Cohen d=-0.10). Among ICS users, no significant differences between the study groups were found over time in terms of the proportion of participants who were dispensed antimycotics (t
=0.29, 95% CI -0.40 to 0.54; P=.76; Cohen d=0).
This study provides preliminary evidence that the SARA eHealth intervention might have the potential to decrease exacerbation rates and improve medication adherence among patients with asthma and COPD.
The economic costs of mental disorders for society are huge. Internet-based interventions are often coined as cost-effective alternatives to usual care, but the evidence is mixed.
The aim was to ...review the literature on the cost-effectiveness of internet interventions for mental disorders compared with usual care and to provide an estimate of the monetary benefits of such interventions compared with usual care.
A systematic review and meta-analysis of randomized controlled trials was conducted, which included participants with symptoms of mental disorders; investigated a telephone- or internet-based intervention; included a control condition in the form of treatment as usual, psychological placebo, waiting list control, or bibliotherapy; reported outcomes on both quality of life and costs; and included articles published in English. Electronic databases such as PubMed (including MEDLINE), Embase, Emcare, PsycINFO, Web of Science, and the Cochrane Library were used. Data on risk of bias, quality of the economic evaluation, quality-adjusted life years, and costs were extracted from the included studies, and the incremental net benefit was calculated and pooled.
The search yielded 6226 abstracts, and 37 studies with 14,946 participants were included. The quality of economic evaluations of the included studies was rated as moderate, and the risk of bias was high. A random-effects approach was maintained. Analyses suggested internet interventions were slightly more effective than usual care in terms of quality-adjusted life years gain (Hedges g=0.052, 95% CI 0.010-0.094; P=.02) and equally expensive (Hedges g=0.002, 95% CI -0.080 to 0.84; P=.96). The pooled incremental net benefit was US $255 (95% CI US $91 to US $419; P=.002), favoring internet interventions over usual care. The perspective of the economic evaluation and targeted mental disorder moderated the results.
The findings indicate that the cost-effectiveness of internet interventions for mental disorders compared with a care-as-usual approach is likely, but generalizability to new studies is poor given the substantial heterogeneity. This is the first study in the field of mental health to pool cost-effectiveness outcomes in an aggregate data meta-analysis.
PROSPERO CRD42019141659; https://tinyurl.com/3cu99b34.
Background Multiple sclerosis (MS) is a persistent inflammatory condition impacting the brain and spinal cord, affecting globally approximately 2.8 million individuals. Effective self-management ...plays a crucial role in the treatment of chronic diseases, including MS, significantly influencing health outcomes. A personal health record (PHR) is a promising tool to support self-management, potentially empowering patients and enhancing their engagement in treatment and health. Despite these promising aspects, challenges in implementation persist and PHRs are still a relatively new concept undergoing rapid development. Objective This study aimed to assess the feasibility and usability of the PHR. Secondary objectives included evaluating implementation determinants, and exploring preliminary effects on quality of care for both patients and healthcare professionals (HCPs), self-management, self-efficacy for patients, job satisfaction, efficiency, and demand for HCPs, and preliminary effects on costs and health-related quality of life. Methods This study had a mixed-methods design. Quantitative data of patients ( n = 80) and HCPs ( n = 12) were collected via self-reported questionnaires at baseline (T0), after one year (T1), and after two years (T2). One focus group interview was conducted at T2 with patients ( n = 7), and another one with HCPs ( n = 4), to get a more in-depth understanding of the feasibility and usability of the PHR via the Unified Theory of Acceptance and Use of Technology framework, and to further explore the secondary objectives in-depth. Results Most patients never logged in during the first year and logged in a couple of times per year during the second year, averaging around 15 min per log-in session. The HCPs mainly logged in a couple of times per year over the two years with an average use of six minutes per session. Patient usability and satisfaction scores were below average and moderate, respectively: with SUS-scores of 59.9 ( SD = 14.2, n = 33) at T1 and 59.0 ( SD = 16.3, n = 37) at T2, and CSQ-8 scores of 21.4 ( SD = 5.0, n = 34) at T1, and 22.1 ( SD = 5.0, n = 39) at T2. HCPs had similar usability and satisfaction scores. Multiple facilitators and barriers were identified by both patients and HCPs, such as (in)sufficient knowledge of how to use the PHR, lack of staff capacity and ICT obstacles. No significant differences were found in the preliminary effects. Qualitative data showed, among others, that both patients and HCPs saw the benefit of the PHR in terms of performance expectancy, by gaining more insight into health and health data, but challenges remained regarding effort expectancy, such as log-in issues and experiencing difficulties with information retrieval. Conclusion The feasibility and usability were considered moderate by patients and HCPs; however, potential regarding the performance of the PHR was observed. Implementation challenges, such as the complexity of usage, lowered the adoption of the PHR. The evolving nature of PHRs requires ongoing evaluation and adaptation to optimize their potential benefits. Utilizing a participatory design approach and a dedicated implementation team could help in achieving this optimization, ultimately enhancing their adoption.
Abstract
Background
In adult IBD patients vedolizumab has proven to be effective but prospective studies in paediatric IBD (PIBD) patients have not been performed. Available retrospective studies in ...PIBD are promising regarding corticosteroid-free remission (CFR) rates, especially in refractory ulcerative colitis (UC) patients. Vedolizumab is therefore to be considered in refractory PIBD patients failing anti-TNF. Data on endoscopic findings and long-term follow-up are especially scarce. We investigated the long-term clinical and endoscopic follow-up in PIBD patients.
Methods
For this retrospective per protocol study PIBD patients receiving vedolizumab from 2015–2018 in a tertiary centre were included. Most patients received 300 mg at week 0, 2, 6 and every 8 weeks thereafter, and had oral prednisolone as bridging therapy. At each infusion visit clinical disease activity scores, routine laboratory parameters and serum samples were collected. Endoscopy was performed after at least 3 infusions.
Results
In total, 22 PIBD patients (12 UC, 7 CD and 3 IBDU) with a median age of 15.3 years (IQR 12.3–17.1) received vedolizumab after previous anti-TNF failure (73% pharmacodynamic, 13% immunogenic, 4% pharmacokinetic failure). Median follow-up after start of vedolizumab was 60 weeks (IQR 18–75). 1-year follow-up data were available in 17 patients. Five patients were transferred to adult care within 1 year after starting vedolizumab treatment. Vedolizumab was discontinued in 42% (5/12) of UC/IBDU patients compared with 80% (4/5) of CD patients (77 and 23 weeks of median therapy duration, respectively). Corticosteroid-free remission (CFR) rates, defined as no use of corticosteroids and a PUCAI < 10 or PCDAI < 12.5, were 25% in UC/IBDU and 0% in CD at 14 weeks. After 54 weeks 25% of the UC/IBDU patients were in CFR.
Figure 1.
Endoscopy was performed in 12 patients (11 UC/IBDU, 1 CD) after a median follow-up of 23 weeks (IQR 19–29), which showed mucosal healing (Mayo score 0) in 36% of UC/IBDU patients (n = 4) but active disease in the one CD patient. At last follow-up 37% (8/22) of patients needed a surgical resection (2 in CD and 6 colectomies in UC/IBDU) after a median therapy duration of 38 weeks (IQR 23–60). Analysis of trough levels is currently ongoing.
Conclusions
In this group of refractory PIBD patients 25% of UC and none of the CD patients had CFR at 14 weeks. After 54 weeks 25% of UC patients was in CFR. Mucosal healing was shown in 36% of UC/IBDU patients. Future studies including vedolizumab trough levels and subsequent optimal dosing in PIBD are essential.
Abstract
Background
Crohn’s disease (CD) and ulcerative colitis (UC) are characterized by intestinal infiltration of pathogenic effector CD4+ T cells. The defects driving loss of T-cell regulation ...vary between patients and remain undefined. Previously, we have shown that in human intestine, 20–40% of effector (CD62LnegCD4+) T cells express TIGIT (T cell immunoglobulin and ITIM domain), an inhibitory receptor modulating dendritic cell and T-cell function. TIGIT expression is enriched in circulating gut-homing CD38+ effector T cells in healthy controls while in a subgroup of IBD patients with active intestinal inflammation, frequencies of inhibitory TIGIT+CD38+ effector T cells are decreased and associated with earlier relapse of disease. Here we hypothesized that gut-homing effector T cells lacking TIGIT (TIGITneg) are pathogenic mediators of intestinal inflammation in IBD and assessed whether patients with low frequencies have a distinctive disease immunotype.
Methods
In the Rotterdam PIBD-SETQuality cohort of newly diagnosed pediatric IBD patients (CD: n=50; UC: n=25), patients with suspicion of IBD but negative diagnosis (n=17) and age-matched healthy controls (HC: n=22), we monitored TIGIT+ and TIGITnegCD38+ effector T cells in peripheral blood, collected plasma at diagnosis and during therapy and phenotyped intestinal T cells.
Results
At diagnosis, 50% of CD patients had strongly reduced frequencies of inhibitory TIGIT+CD38+ effector T cells compared to UC patients and HC. CD patients with reduced frequencies of inhibitory TIGIT+CD38+ effector T cells had higher plasma IFN-γ concentrations and 53% of them experienced a disease relapse by 1 year versus 25% for CD patients with normal TIGIT+CD38+effector frequencies. In keeping with our hypothesis that TIGITneg gut-homing effector T cells are pathogenic, absence of TIGIT expression identified CD38+ effector T cells enriched in recent proliferation and having high expression of chemokine receptors associated with inflammatory non-classical T helper-1 IFNγ highIL-17Alow producing (Th1*) cells. Moreover, intestinal TIGITnegCD4+ T cells of CD patients contained higher frequencies of IFNγ and IL-17A producing cells than TIGIT+CD4+ T cells. In order to identify the factors that drive differentiation of the pathogenic Th1* cells, inhibitory TIGIT+CD38+ effector T cells from HC were exposed to an array of IBD-associated cytokines in vitro. Only IL-12p70, a known driver of IFNγ, could convert inhibitory TIGIT+CD38+ effector T cells into their TIGITneg proinflammatory counterpart.
Conclusion
We identify TIGITneg gut-homing effector T cells, enriched in Th1* cells, as potential drivers of intestinal inflammation in a subgroup of CD, but not UC patients, with a more severe disease course.
Abstract
Background
In inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), CD4+ T cell-responses to unknown microbial antigens drive intestinal inflammation. ...Both hypo- or hyperactive anti-microbial innate immunity may underlie these pathogenic T-cell responses. Previously, IgG and T-cell responses to Lachnospiraceae flagellins were detected in spontaneously colitic mice with an innate immune defect and adult CD patients with complicated disease. However, whether these IgG responses occur in therapy-naïve pediatric patients and whether they relate to hypo- or hyperresponsiveness is unknown. We hypothesize that, at diagnosis, a subgroup of pediatric CD patients has elevated anti-Lachnospiraceae flagellin IgG and concomitant inflammatory flagellin-specific T-cell responses associating with insufficient anti-microbial innate immunity.
Methods
Plasma IgG reactivity to 20 flagellins from Lachnospiraceae that colonize mouse and human gut was measured in therapy-naïve pediatric IBD patients (CD n=49; UC n=16), non-IBD (n=12) and age-matched healthy controls (HC n=17). CD patients were divided in two groups: ‘flagellin-hi’ (elevated IgG to 11-20 flagellins) and ‘flagellin-lo’ (elevated IgG to 0-10 flagellins), whose immunological and clinical profiles were compared.
Results
The proportion of flagellin-hi patients was higher in CD (41%) compared to UC (6%), non-IBD (8%) and HC (6%). In CD patients, clinical disease activity score, CRP and ESR did not relate to flagellin reactivity. Compared to flagellin-lo patients, flagellin-hi patients had increased frequencies of inflammatory gut-homing (CD38+CD62Lneg) circulating CD4+ T cells. Crucially, flagellin-hi patients had high frequencies of circulating flagellin-specific CD4+ T cells. Although high anti-flagellin IgG reactivity associated with increased flagellin-specific- and gut-homing- T-cell frequencies in the circulation, it associated with very limited immune cell infiltration, epithelial damage and phosphorylated NFκB in colonic biopsies on histology. Moreover, the plasma concentration of EN-RAGE, a neutrophil-derived protein, was decreased in flagellin-hi compared -lo patients.
Conclusion
In sum, a subgroup of pediatric therapy-naïve CD patients has high IgG responses to Lachnospiraceae-derived flagellins. While these flagellin-hi patients have higher frequencies of circulating gut-homing and flagellin-specific CD4+ T cells, they have lower colonic histological disease activity and NFκB activation, possibly suggesting insufficient innate immune cell activation and/or infiltration. Together, our data raise the question whether the enhanced anti-Lachnospiraceae adaptive immune response in a subgroup of CD patients may be driven by insufficient local innate immunity.
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