De-Escalation of Anti-Tumor Necrosis Factor Alpha Agents and Reduction in Adverse Effects:A Systematic Review

Background: The long-term use of anti-TNF-alpha agents can lead to adverse effects, such as infections and immune-mediated cutaneous reactions. Whether de-escalation by dose reduction or interval lengthening reduces these adverse effects is uncertain. This systematic review aims to compare the incidence of infections and skin manifestations after anti-TNF-alpha dose de-escalation with standard dosing. Methods: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception to January 14, 2022. Randomized controlled trials (RCTs) and observational studies comparing anti-TNF-alpha-de-escalation strategies with standard dosing among patients with inflammatory conditions, that report on infections, skin manifestations, or both, were included. The risk of bias was assessed with the revised Cochrane risk-of bias tool (RCTs) or the Newcastle-Ottawa scale (non-RCTs). Results: Fourteen RCTs and six observational studies (or 2706 patients) were included. Eight RCTs had low risk of bias or some concerns. Four non-RCTs were of good methodological quality. The studies described patients with axial spondyloarthritis (8 studies, 780 patients), rheumatoid arthritis (7 studies, 1458 patients), psoriasis (3 studies, 332 patients), or inflammatory bowel disease (2 studies, 136 patients). De-escalation strategies included interval lengthening (12 studies, 1317 patients), dose reduction (6 studies, 1130 patients), or both (2 studies, 259 patients). Overall, the occurrence of infections and skin manifestations did not differ between standard treatment and de-escalation. The disappearance of infections or skin manifestations after de-escalation was only reported in two studies. The majority of studies focused on etanercept and adalimumab. Heterogeneity in reporting of infections and skin manifestations precluded metaanalysis. Conclusion: We found that anti-TNF-alpha de-escalation does not reduce infections or skin reactions. A de-escalation strategy should not be recommended for the sole purpose of reducing drug-related adverse effects. The meticulous documentation of adverse effects is recommended to further address this question

Severe acute hepatitis and acute liver failure of unknown origin in children : a questionnaire-based study within 34 paediatric liver centres in 22 European countries and Israel, April 2022

Publisher Copyright: © 2022 European Centre for Disease Prevention and Control (ECDC). All rights reserved.To detect potential concern about severe acute hepatitis in children, we conducted a survey among 50 ERN RARE-LIVER centres. By 26 April 2022, 34 centres, including 25 transplant centres, reported an estimated median of 3-5, 0-2 and 3-5 cases in 2021, 2020 and 2019 and a mean of 2 (range: 0-8) cases between January and April 2022 (mean in 10 large liver transplant centres: 3). Twelve centres reported suspicion of an increase, but no rise. Following a report by the United Kingdom (UK) on 5 April 2022 on the occurrence of cases of severe acute hepatitis in children aged 16 years or under, the World Health Organization (WHO) raised concerns about the possibility of an epidemic [1,2]. By 21 April, 169 possible or confirmed cases were reported fulfilling the WHO case definition [3]. The cause of the hepatitis is unknown but a link to a virus infection has been suggested due to the epidemiological pattern of cases [4,5]. The hepatitis can progress to paediatric acute liver failure (pALF) necessitating urgent liver transplantation to avoid multi-organ failure [6]. We intended to assess whether a rise in incidence of severe acute hepatitis or pALF could be observed between 1 January and 26 April 2022 in comparison to previous years, within the European Reference Network on Hepatological Diseases (ERN RARE-LIVER) [7].Peer reviewe

Severe acute hepatitis and acute liver failure of unknown origin in children:a questionnaire-based study within 34 paediatric liver centres in 22 European countries and Israel, April 2022

To detect potential concern about severe acute hepatitis in children, we conducted a survey among 50 ERN RARE-LIVER centres. By 26 April 2022, 34 centres, including 25 transplant centres, reported an estimated median of 3-5, 0-2 and 3-5 cases in 2021, 2020 and 2019 and a mean of 2 (range: 0-8) cases between January and April 2022 (mean in 10 large liver transplant centres: 3). Twelve centres reported suspicion of an increase, but no rise. Following a report by the United Kingdom (UK) on 5 April 2022 on the occurrence of cases of severe acute hepatitis in children aged 16 years or under, the World Health Organization (WHO) raised concerns about the possibility of an epidemic [1,2]. By 21 April, 169 possible or confirmed cases were reported fulfilling the WHO case definition [3]. The cause of the hepatitis is unknown but a link to a virus infection has been suggested due to the epidemiological pattern of cases [4,5]. The hepatitis can progress to paediatric acute liver failure (pALF) necessitating urgent liver transplantation to avoid multi-organ failure [6]. We intended to assess whether a rise in incidence of severe acute hepatitis or pALF could be observed between 1 January and 26 April 2022 in comparison to previous years, within the European Reference Network on Hepatological Diseases (ERN RARE-LIVER) [7]

Indeterminate pediatric acute liver failure:Clinical characteristics of a temporal cluster of five children in the Netherlands in the spring of 2022

There is increasing global concern of severe acute hepatitis of unknown etiology in young children. In early 2022, our center for liver transplantation in the Netherlands treated five children who presented in short succession with indeterminate acute liver failure. Four children underwent liver transplantation, one spontaneously recovered. Here we delineate the clinical course and comprehensive diagnostic workup of these patients. Three of five patients showed a gradual decline of liver synthetic function and had mild neurological symptoms. Their clinical and histological findings were consistent with hepatitis. These three patients all had a past SARS-CoV-2 infection and two of them were positive for adenovirus DNA. The other two patients presented with advanced liver failure and encephalopathy and underwent dialysis as a bridge to transplantation. One of these children spontaneously recovered. We discuss this cluster of patients in the context of the currently elevated incidence of severe acute hepatitis in children

Dendritic cell-bound IgE functions to restrain allergic inflammation at mucosal sites

Antigen-mediated crosslinking of Immunoglobulin E (IgE) bound to mast cells/basophils via FcεRI, the high affinity IgE Fc-receptor, is a well-known trigger of allergy. In humans, but not mice, dendritic cells (DCs) also express FcεRI that is constitutively occupied with IgE. In contrast to mast cells/basophils, the consequences of IgE/FcεRI signals for DC function remain poorly understood. We show that humanized mice that express FcεRI on DCs carry IgE like non-allergic humans and do not develop spontaneous allergies. Antigen-specific IgE/FcεRI crosslinking fails to induce maturation or production of inflammatory mediators in human DCs and FcεRI-humanized DCs. Furthermore, conferring expression of FcεRI to DCs decreases the severity of food allergy and asthma in disease-relevant models suggesting anti-inflammatory IgE/FcεRI signals. Consistent with the improved clinical parameters in vivo, antigen-specific IgE/FcεRI crosslinking on papain or LPS-stimulated DCs inhibits the production of pro-inflammatory cytokines and chemokines. Migration assays confirm that the IgE-dependent decrease in cytokine production results in diminished recruitment of mast cell progenitors; providing a mechanistic explanation for the reduced mast cell-dependent allergic phenotype observed in FcεRI-humanized mice. Our study demonstrates a novel immune regulatory function of IgE and proposes that DC-intrinsic IgE signals serve as a feedback mechanism to restrain allergic tissue inflammation

Proton Pump Inhibitor Use, Fatigue, and Health-Related Quality of Life in Kidney Transplant Recipients:Results From the TransplantLines Biobank and Cohort Study

Rationale &amp; Objective: Prior studies report that the use of proton pump inhibitors (PPIs) can adversely affect gut microbiota and gastrointestinal uptake of micronutrients, in particular iron and magnesium, and are used frequently by kidney transplant recipients. Altered gut microbiota, iron deficiency, and magnesium deficiency have been implicated in the pathogenesis of chronic fatigue. Therefore, we hypothesized that PPI use may be an important and underappreciated cause of fatigue and reduced health-related quality of life (HRQoL) in this population. Study Design: Cross-sectional study. Setting &amp; Participants: Kidney transplant recipients (≥1 year after transplantation) enrolled in the TransplantLines Biobank and Cohort Study. Exposure: PPI use, PPI type, PPI dosage, and duration of PPI use. Outcome: Fatigue and HRQoL, assessed using the validated Checklist Individual Strength 20 Revised questionnaire and Short Form-36 questionnaire. Analytical Approach: Logistic and linear regression. Results: We included 937 kidney transplant recipients (mean age 56 ± 13 years, 39% female) at a median of 3 (1-10) years after transplantation. PPI use was associated with fatigue severity (regression coefficient 4.02, 95% CI, 2.18 to 5.85, P &lt; 0.001), a higher risk of severe fatigue (OR 2.05, 95% CI, 1.48 to 2.84, P &lt; 0.001), lower physical HRQoL (regression coefficient −8.54, 95% CI, −11.54 to −5.54, P &lt; 0.001), and lower mental HRQoL (regression coefficient −4.66, 95% CI, −7.15 to −2.17, P &lt; 0.001). These associations were independent of potential confounders including age, time since transplantation, history of upper gastrointestinal disease, antiplatelet therapy, and the total number of medications. They were present among all individually assessed PPI types and were dose dependent. Duration of PPI exposure was only associated with fatigue severity. Limitations: Residual confounding and inability to assess causal relationships. Conclusions: PPI use is independently associated with fatigue and lower HRQoL among kidney transplant recipients. PPI use might be an easily accessible target for alleviating fatigue and improving HRQoL among kidney transplant recipients. Further studies examining the effect of PPI exposure in this population are warranted. Plain-Language Summary: In this observational study, we investigated the association of proton pump inhibitors with fatigue and health-related quality of life among kidney transplant recipients. Our data showed that proton pump inhibitors were independently associated with fatigue severity, severe fatigue, and lower physical and mental health-related quality of life. These associations were present among all individually assessed proton pump inhibitor types and were dose dependent. While we await future studies on this topic, proton pump inhibitor use might be an easily accessible target for alleviating fatigue and improving health-related quality of life among kidney transplant recipients.</p

Pediatric acute liver failure:variations in referral timing are associated with disease subtypes

In pediatric acute liver failure (PALF), rapid referral to a transplant center (TC) is advocated. Clinical variability of PALF may influence referral timing. We aimed to analyze early or late timing of referral in relation to clinical characteristics and outcome in PALF. We conducted a retrospective, single-center, comparative analysis of clinical and liver function parameters in two PALF cohorts (n = 23 per cohort): cohort 1 (early referral, duration of in-patient care before referral (DCR) <7 days) vs. cohort 2 (late referral, DCR a parts per thousand yenaEuro parts per thousand 7 days). Compared to late referrals, patients referred early were more frequently non-icteric and encephalopathic at initial presentation (n = 14 vs. 5 and n = 13 vs. 4, each p <0.05). Early referred PALF patients had lower hepatic encephalopathy (HE) grades and bilirubin (grade 1 vs. 2, p <0.02; 215 vs. 439 mu mol/l, p <0.001, respectively) but higher alanine aminotransferase (ALAT) levels (4,340 vs. 963 U/l, p <0.001). Cumulative poor prognostic indicators were lower in early referrals (2 vs. 4, p <0.001). In multivariate analysis, subacute liver failure (SLF > 7 days between disease onset and development of encephalopathy) was independently associated with late referral (relative risk 9.48; 95 % CI 1.37-64.85, p <0.02). Differences in survival to discharge were not significant. Conclusion: In PALF, referral timing variability is associated with distinct clinical and liver function patterns. Early recognition of prognostic indicators and of SLF may help to improve referral timing and thus PALF management

Pediatric Inflammatory Bowel Disease

Inflammatory bowel diseases (IBDs) are chronic, immune-mediated disorders that include Crohn's disease and ulcerative colitis. A pediatric onset of disease occurs in about 10% of all cases. Clinical presentation of IBD with rectal bleeding or perianal disease warrants direct referral for endoscopic evaluation. In the absence of red-flag symptoms, a combination of patient history and blood and fecal biomarkers can help to distinguish suspected IBD from other causes of abdominal pain or diarrhea. The therapeutic management of pediatric IBD has evolved by taking into account predictors of poor outcome, which justifies the upfront use of anti-tumor necrosis factor therapy for patients at high risk for complicated disease. In treating patients with IBD, biochemical or endoscopic remission, rather than clinical remission, is the therapeutic goal because intestinal inflammation often persists despite resolution of abdominal symptoms. Pediatric IBD comes with unique additional challenges, such as growth impairment, pubertal delay, the psychology of adolescence, and development of body image. Even after remission has been achieved, many patients with IBD continue to experience nonspecific symptoms like abdominal pain and fatigue. Transfer to adult care is a well-recognized risk for disease relapse, which highlights patient vulnerability and the need for a transition program that is continued by the adult-oriented IBD team. The general pediatrician is an invaluable link in integrating these challenges in the clinical care of patients with IBD and optimizing their outcomes. This state-of-the-art review aims to provide general pediatricians with an update on pediatric IBD to facilitate interactions with pediatric gastrointestinal specialists

Involvement of the iNKT cell pathway is associated with early-onset eosinophilic esophagitis and response to allergen avoidance therapy

OBJECTIVES: Recent experimental evidence suggests that environmental microbial factors early in life determine susceptibility to allergic diseases through inappropriate chemotaxis and local activation of CD1d-restricted, invariant chain natural killer T (iNKT) cells. In this study, we analyzed the involvement of these pathways in pediatric patients with eosinophilic esophagitis (EoE) before and after dietary allergen elimination. METHODS: mRNA expression levels of components of the C-X-C motif chemokine ligand 16 (CXCL16)–iNKT–CD1d axis were compared in esophageal biopsies from EoE patients vs. normal or inflammatory controls and before and after treatment. RESULTS: CXCL16, iNKT cell–associated cell marker Vα24, and CD1d were significantly upregulated in esophageal biopsies from EoE patients and correlated with the expression of inflammatory mediators associated with allergy. Upregulation of each of these factors was significantly more pronounced in patients aged < 6 years at diagnosis, and this early-onset EoE subpopulation was characterized by a more prominent food allergic disease phenotype in a cohort-wide analysis. Successful, but not unsuccessful, treatment of early-onset EoE patients with dietary elimination of instigating allergens led to reduction in infiltrating iNKT cells and complete normalization of mRNA expression levels of CXCL16 and CD1d. CONCLUSIONS: Our observations place iNKT cells at the center of allergic inflammation associated with EoE, which could have profound implications for our understanding, treatment and prevention of this and other human allergic diseases