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.
Abstract
Background
Paediatric-onset IBD (PIBD) patients often present with more serious disease than adults and are exposed to intensive treatment, which may cause rare but very severe ...complications. Due to the rarity of these events available data are limited, resulting in prevention and treatment recommendations based on very low evidence or even absence of any recommendations. Therefore, an international study is essential to obtain data on incidence and to characterise these complications. With the setup of a safety registry for rare and severe complications in PIBD we aim to improve knowledge on incidence and risk factors of rare and severe complications.
Methods
Paediatric gastroenterologists in 26 different countries reply monthly to an electronic survey to indicate whether they have seen one of 10 predetermined complications in an IBD patient <19 years of age. It also enables the physician to report another, in their opinion rare and severe, complication. Information about disease, previous therapies and specific complications is collected for each registered complication. Additionally, participating physicians annually report the number of new and current PIBD patients under their care. The calculation of the incidence per country and region uses validated population statistics from Eurostat and the Poisson distribution for rare events.
Results
In this ongoing registry 1952 responses were received from October 2016 – October 2018 based on responses of 128 paediatric gastroenterologists (response rate 80%). A total of 88 categorised complications were reported.
Among the 7 reported cases of a venous thromboembolism were 2 cases of a venous sinus thrombosis. All were having an exacerbation of IBD and in only two patients another risk factor was present. The two reported cases of hemophagocytic lymphohistiocytosis were both using azathioprine and mesalazine, had a primary EBV infection and fully recovered. Other reported complications vary from acute psychosis to an air embolism during colonoscopy.
Conclusions
Since the start of this registry 88 rare and severe complications in PIBD patients were prospectively identified. Besides the identification of a variety of severe adverse events, this enables understanding possible causes, management and outcomes of rare but severe events in PIBD. Moreover, this may enable prevention of these events. Combined with the denominator data that are being collected this will provide data on the incidence of these severe outcomes.
To evaluate the development and implementation of clinical practice guidelines for the management of depression globally.
We conducted a systematic review of existing guidelines for the management of ...depression in adults with major depressive or bipolar disorder. For each identified guideline, we assessed compliance with measures of guideline development quality (such as transparency in guideline development processes and funding, multidisciplinary author group composition, systematic review of comparative efficacy research) and implementation (such as quality indicators). We compared guidelines from low- and middle-income countries with those from high-income countries.
We identified 82 national and 13 international clinical practice guidelines from 83 countries in 27 languages. Guideline development processes and funding sources were explicitly specified in a smaller proportion of guidelines from low- and middle-income countries (8/29; 28%) relative to high-income countries (35/58; 60%). Fewer guidelines (2/29; 7%) from low- and middle-income countries, relative to high-income countries (22/58; 38%), were authored by a multidisciplinary development group. A systematic review of comparative effectiveness was conducted in 31% (9/29) of low- and middle-income country guidelines versus 71% (41/58) of high-income country guidelines. Only 10% (3/29) of low- and middle-income country and 19% (11/58) of high-income country guidelines described plans to assess quality indicators or recommendation adherence.
Globally, guideline implementation is inadequately planned, reported and measured. Narrowing disparities in the development and implementation of guidelines in low- and middle-income countries is a priority. Future guidelines should present strategies to implement recommendations and measure feasibility, cost-effectiveness and impact on health outcomes.
Abstract
Background
Chronicity of inflammatory bowel disease (IBD) is driven by reactivation of inflammatory memory CD4+ T helper (Th) cells which activate an inflammatory cascade involving innate ...immune cells and structural intestinal tissue cells. Because of disease heterogeneity, novel treatment strategies tailored to more precisely target the patient’s individual immune defect are required to prevent disease reactivation. We hypothesize that analysis of changes in circulating inflammatory protein abundance combined with phenotyping of circulating Th cells allow to dissect underlying immune pathogenesis and aim to stratify pediatric IBD patients accordingly.
Methods
We performed plasma analysis of 92 inflammatory proteins in a cohort of pediatric IBD patients (CD: n=62; UC/IBD-U: n=20), patients with suspicion of IBD but negative diagnosis (n=13) and age-matched healthy controls (HC: n=30). Peripheral blood was obtained at diagnosis and after induction treatment (t=10–14 weeks). Plasma protein concentrations were assessed with Olink Proximity Extension Assay technology® and Th cells were analyzed with flow cytometry.
Results
Thirty-six plasma proteins discriminated pediatric IBD patients from HC. CD and UC/IBD-U patients shared increased abundance of 17 proteins amongst which interleukin-6 and oncostatin-M. Increased abundance of the Th1 cytokine interferon-γ was strictly associated with CD while Th17-associated interleukin-17A was significantly more abundant in UC/IBD-U. Hierarchical clustering of plasma protein profiles discriminated 2 clusters of UC patients with different clinical disease activity and disease extent. In CD, three patient clusters were identified. CD#3 patients had lower clinical disease activity, lower C-reactive protein and higher blood albumin concentrations, while clusters CD#1 and CD#2 had comparable clinical parameters. CD#1 patients had higher abundance of 14 proteins associated with neutrophil function and interferon-γ signaling while CD#2 patients had a marked increase in frequencies of activated (HLA-DR+) memory Th cells. The three CD clusters responded differently to therapy with CD#1 patients exhibiting more modulated proteins and greater fold changes, CD#2 patients showing intermediate modulation and CD#3 patients exhibiting only a few changes.
Conclusion
Combined plasma immune protein and circulating Th cell profiling combined with in depth clinical monitoring discriminates subgroups of pediatric IBD patients during active disease which differ in their response to induction therapy.
Abbreviations: CD: Crohn’s disease; UC: ulcerative colitis; IBD-U: IBD-unclassified.
Abstract
Background
The consequences of paediatric IBD (PIBD), such as growth failure, bowel resection at young age and a lifelong risk of treatment-related adverse events may hugely influence the ...patient’s further development and quality of life. Unfortunately, we are still not able to predict which patients are at risk of developing a complicated disease course. To investigate this, large prospective international studies withlong-term follow-up are needed. In this first global cohort, we aim to evaluate which patients are at risk based on patient and disease characteristics, immune pathology and environmental factors.
Methods
In this international prospective observational study, children and adolescents diagnosed with IBD <18 years are included at disease diagnosis with the intention of up to 20 years follow-up following a visit schedule that is in line with standard PIBD care. Patient and disease characteristics, as well as results of investigations, are collected at baseline and during follow-up. In addition, environmental factors are being assessed. In specific centres with the ability to perform extensive immunological analyses, biomaterial is being collected in therapy naïve patients at baseline and during follow-up.
Results
PIBD patients data from in 14 centres in the UK (UK), The Netherlands (NL), Italy, Israel, and Malaysia are recruiting 12–13 patients per month. Ten extra centres (in 4 new countries) are preparing for their first recruitment with an estimated 19 extra patients per month. Well organised data management and responsive sites led to a completion rate of 76% of the 1700 raised queries. To date 178 PIBD patients have been recruited which equals 18% of the target number. They have a varied ethnicity (69.9% white; 13.9% South Asian; 1,7% South East Asian; 5.2% black; 0.6% hispanic/latino; 8.7% mixed race). Median length of follow-up of these patients is 8.5 months. The median PCDAI and PUCAI scores at baseline are 25 (IQR 15) and 45 (IQR 35) in CD and UC, respectively. Median baseline endoscopy scores showed a median SES-CD score of 10 (IQR 10) and UCEIS of 4 (IQR 2.5). Comparing data between countries show that the use of maintenance therapy is equal with 62% and 61% on an immunomodulator at 6 months follow-up in UK and NL, respectively. Analysis of international and racial differences regarding presenting phenotype, performed diagnostics and induction therapies are ongoing.
Conclusions
As the first global inception cohort including data from European and Asian countries, this will reveal valuable data on standard clinical practice and immune pathology, facilitate comparisons on diagnostic and therapeutic strategies between countries and provide opportunities to compare findings with other national cohorts.
Background Although effective in superficial basal cell carcinoma (BCC), the treatment effect of photodynamic therapy (PDT) in nodular BCC (nBCC) is still questionable. The relation between tumor ...thickness and PDT failure is unclear. Objective We sought to compare long-term effectiveness of fractionated 20% 5-aminolevulinic acid (ALA)-PDT with prior partial debulking versus surgical excision in nBCC. The effect of tumor thickness on ALA-PDT failure was analyzed. Methods 173 primary, histologically proven nBCCs in 151 patients were randomized to fractionated ALA-PDT (n = 85) or surgical excision (n = 88). Two PDT illuminations were performed with a 1-hour interval. Follow-up was at least 5 years posttreatment. Clinical recurrences were confirmed histologically. Results A total of 171 nBCCs were treated and had a median follow-up of 67 months (range 0-106). At 60 months, 23 tumors had recurred in the ALA-PDT group and 2 tumors in the surgical excision group. Cumulative recurrence probabilities 5 years posttreatment were 30.7% (95% confidence interval CI 21.5%-42.6%) for ALA-PDT and 2.3% (95% CI 0.6%-8.8%) for surgical excision ( P < .0001). Two tumors in the ALA-PDT group recurred at 72 and 91 months posttreatment. Cumulative probability of recurrence-free survival post-PDT was 65.0% (95% CI 51%-76%) for nBCC measuring greater than 0.7 mm in thickness and 94.4% (95% CI 67%-99%, P = .018) for tumors less than or equal to 0.7 mm. Limitations Tumor thickness on punch biopsy specimen might differ from the total lesion thickness. Conclusions In nBCC, 5-year cumulative probability of recurrence after surgical excision is lower than after fractionated ALA-PDT with prior debulking. Although surgical excision remains the gold standard of treatment, PDT might be an alternative for inoperable patients with thin (≤0.7 mm) nBCC.
Treatment guidelines for paediatric Crohn's disease CD suggest early use of anti-tumour necrosis factor alpha anti-TNFα in high-risk individuals. The aim is to evaluate the effect of early anti-TNF ...in a real-world cohort.
Children with newly diagnosed CD were prospectively recruited at 28 participating sites of the international observational PIBD-SETQuality study. Outcomes were compared at 3 months, 1 and 2 years between patients receiving early anti-TNF <90 days after diagnosis and those not receiving early anti-TNF. Outcomes included sustained steroid-free remission SSFR without treatment intensification specified as SSFR* and sustained steroid-free mild/inactive disease without treatment intensification specified as SSFMI*. Penalised logistic regression model-based standardisation was applied to estimate the relative risks RR of early therapy on outcomes. RRs were estimated for high-risk and low-risk patients, based on presence of predictors of poor outcome POPOs and disease activity at diagnosis.
In total, 331 children (median age 13.9 years IQR 12.2-15.3) were enrolled, with 135 41% receiving early anti-TNF. At 1 year, patients on early anti-TNF had higher rates of SSFR* 30% vs 14%, p <0.001 and SSFMI* 69% vs 33%, p <0.001, with RRs of 2.95 95% CI 1.63-5.36 and 4.67 95% CI 2.46-8.87, respectively. At 1 year, the RRs for SSFMI* were higher, and statistically significant in high-risk patients, i.e. those with moderate/severe disease compared with mild/inactive disease at diagnosis (5.50 95% CI 2.51-12.05 vs 2.91 95% CI 0.92-9.11), and those with any POPO compared with no POPO (5.05 95% CI 2.45-10.43 vs 3.41 95% CI 0.54-21.7).
In this cohort of children with newly-diagnosed CD, early anti-TNF demonstrated superior effectiveness in high-risk patients.
Background: Individuals with eating disorders show deficits in neuropsychological functioning which might preexist and underlie the etiology of the eating disorders and influence relapse. Deficits in ...cognitive flexibility, i.e. set-shifting and central coherence, might perpetuate the symptoms. Cognitive remediation therapy (CRT) was developed to improve cognitive flexibility, thereby increasing the likelihood of improved outcome. The focus of CRT is on how patients think, rather than on what patients think. The present study investigated the effectiveness of CRT for patients with a severe or enduring eating disorder by means of a randomized controlled trial comparing intensive treatment as usual (TAU) to CRT plus TAU. Methods: Eighty-two patients were randomly assigned to CRT plus TAU (n = 41) or TAU alone (n = 41). Outcome measures were set-shifting, central coherence, eating disorder and general psychopathology, motivation, quality of life and self-esteem. Assessments were performed at baseline (n = 82) and after 6 weeks (T1; n = 75) and 6 months (T2; n = 67). Data were analyzed by means of linear mixed model analyses. Results: Patients who received CRT in addition to TAU improved significantly more with regard to eating disorder-related quality of life at the end of treatment (T1) and eating disorder psychopathology at follow-up (T2), compared to those who received TAU only. Moreover, moderator analyses revealed that patients with poor baseline set-shifting abilities benefited more from CRT than patients with no deficits in set-shifting abilities at baseline; the quality of life of the former group was higher than that of the latter at follow-up. Conclusions: CRT seems to be promising in enhancing the effectiveness of concurrent treatment.
A better understanding of prognostic factors within the heterogeneous spectrum of pediatric Crohn’s disease (CD) should improve patient management and reduce complications. We aimed to identify ...evidence-based predictors of outcomes with the goal of optimizing individual patient management.
A survey of 202 experts in pediatric CD identified and prioritized adverse outcomes to be avoided. A systematic review of the literature with meta-analysis, when possible, was performed to identify clinical studies that investigated predictors of these outcomes. Multiple national and international face-to-face meetings were held to draft consensus statements based on the published evidence.
Consensus was reached on 27 statements regarding prognostic factors for surgery, complications, chronically active pediatric CD, and hospitalization. Prognostic factors for surgery included CD diagnosis during adolescence, growth impairment, NOD2/CARD15 polymorphisms, disease behavior, and positive anti-Saccharomyces cerevisiae antibody status. Isolated colonic disease was associated with fewer surgeries. Older age at presentation, small bowel disease, serology (anti-Saccharomyces cerevisiae antibody, antiflagellin, and OmpC), NOD2/CARD15 polymorphisms, perianal disease, and ethnicity were risk factors for penetrating (B3) and/or stenotic disease (B2). Male sex, young age at onset, small bowel disease, more active disease, and diagnostic delay may be associated with growth impairment. Malnutrition and higher disease activity were associated with reduced bone density.
These evidence-based consensus statements offer insight into predictors of poor outcomes in pediatric CD and are valuable when developing treatment algorithms and planning future studies. Targeted longitudinal studies are needed to further characterize prognostic factors in pediatric CD and to evaluate the impact of treatment algorithms tailored to individual patient risk.
PDF
