Lesional Psoriasis is Associated With Alterations in the Stratum Corneum Ceramide Profile and Concomitant Decreases in Barrier Function.

Psoriasis is an inflammatory skin disease associated with an impaired skin barrier. The skin barrier function is dependent on the extracellular lipid matrix which surrounds the corneocytes in the stratum corneum. Ceramides comprise essential components of this matrix.

Guselkumab treatment normalizes the stratum corneum ceramide profile and alleviates barrier dysfunction in psoriasis: results of a randomized controlled trial.

The epidermal inflammation associated with psoriasis drives skin barrier perturbations. The skin barrier is primarily located in stratum corneum (SC). Its function depends on the SC lipid matrix of which ceramides constitute important components.

Prospective multicenter evaluation of adherence to the Dutch guideline for children aged 0-16 years with fever without a source-febrile illness in children (FINCH) study.

Unlabelled: Evaluation of guidelines in actual practice is a crucial step in guideline improvement. A retrospective evaluation of the Dutch guideline for children with fever without an apparent source (FWS) showed 50% adherence in young infants. We prospectively evaluated adherence to the Dutch guideline and its impact on management in current practice.

The oral IRAK4 inhibitors zabedosertib and BAY1830839 suppress local and systemic immune responses in a randomized trial in healthy male volunteers.

This study evaluated and characterized the pharmacological activity of the orally administered interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors BAY1834845 (zabedosertib) and BAY1830839 in healthy male volunteers. Participants received one of either IRAK4 inhibitors or a control treatment (prednisolone 20 mg or placebo) twice daily for 7 days. Localized skin inflammation was induced by topical application of imiquimod (IMQ) cream for 3 days, starting at Day 3 of treatment.

Intradermal substance P as a challenge agent in healthy individuals.

Pharmacological challenge models are deployed to evaluate drug effects during clinical development. Intradermal injection of Substance P (SP) neuropeptide, a potential challenge agent for investigating local mediators, is associated with wheal and flare response mediated by the MRGPRX2 receptor. Although dose-dependent data on SP effects exist, full characterization and information on potential carryover effect after repeated challenge are lacking.

Oral prednisolone suppresses skin inflammation in a healthy volunteer imiquimod challenge model.

Imiquimod (IMQ) is a topical agent that induces local inflammation the Toll-like receptor 7 pathway. Recently, an IMQ-driven skin inflammation model was developed in healthy volunteers for proof-of-pharmacology trials. The aim of this study was to profile the cellular, biochemical, and clinical effects of the marketed anti-inflammatory compound prednisolone in an IMQ model.

First-in-human study to assess the pharmacokinetics, tolerability, and safety of single-dose oxybutynin hydrochloride administered via a microprocessor-controlled intravaginal ring.

Polymeric drug-releasing vaginal rings are useful for both local and systemic administration of drugs via the intravaginal route. Typically, they provide continuous sustained or controlled release of drug(s) over extended time periods, thereby avoiding overdose and improving adherence. This first-in-human study (EudraCT number: 2020-0050044-30) evaluated the pharmacokinetics, safety, and tolerability of a single dose of oxybutynin administered by a novel microprocessor-controlled vaginal ring (MedRing).

Immunosuppression by hydroxychloroquine: mechanistic proof in in vitro experiments but limited systemic activity in a randomized placebo-controlled clinical pharmacology study.

Based on its wide range of immunosuppressive properties, hydroxychloroquine (HCQ) is used for the treatment of several autoimmune diseases. Limited literature is available on the relationship between HCQ concentration and its immunosuppressive effect. To gain insight in this relationship, we performed in vitro experiments in human PBMCs and explored the effect of HCQ on T and B cell proliferation and Toll-like receptor (TLR)3/TLR7/TLR9/RIG-I-induced cytokine production.

[Diaper dermatitis is not always a harmless condition].

Background: Diaper dermatitis in children is common and usually harmless. Often the cause is irritation, a secondary candida infection or eczema, for which treatment is simple and effective. In this paper we show that a therapy resistant diaper dermatitis can be the diagnostic clue to the rare but important diagnosis Langerhans cell histiocytosis (LCH).

Integration of healthy volunteers in early phase clinical trials with immuno-oncological compounds.

Aim: Traditionally, early phase clinical trials in oncology have been performed in patients based on safety risk-benefit assessment. Therapeutic transition to immuno-oncology may open new opportunities for studies in healthy volunteers, which are conducted faster and are less susceptible to confounders. Aim of this study was to investigate to what extent this approach is utilized and whether pharmacodynamic endpoints are evaluated in these early phase trials.

Licogliflozin for nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a study.

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease that may advance to fibrosis and lead to mortality; however, no pharmacotherapy is currently available. We tested the hypothesis that inhibition of both the sodium-glucose cotransporters 1 and 2 with licogliflozin would lead to improvement in NASH. A total of 107 patients with phenotypic or histologic NASH were randomized (1:2:2) to receive oral administration of either placebo (n = 21), licogliflozin 30 mg (n = 43) or 150 mg (n = 43) once daily for 12 weeks.

Administration of an adeno-associated viral vector expressing interferon-β in patients with inflammatory hand arthritis, results of a phase I/II study.

Objective: Inflammatory hand arthritis (IHA) results in impaired function. Local gene therapy with ART-I02, a recombinant adeno-associated virus (AAV) serotype 5 vector expressing interferon (IFN)-β, under the transcriptional control of nuclear factor κ-B responsive promoter, was preclinically shown to have favorable effects. This study aimed to investigate the safety and tolerability of local gene therapy with ART-I02 in patients with IHA.

A novel sustained-release cysteamine bitartrate formulation for the treatment of cystinosis: Pharmacokinetics and safety in healthy male volunteers.

The strict intake regimen of cysteamine bitartrate formulations, associated with side effects, is a concern for the treatment compliance in cystinosis therapy. Therefore, there is a need for a cysteamine formulation with an improved pharmacokinetic profile. This study investigated the pharmacokinetics, safety and tolerability of a new sustained-release cysteamine dosage form, PO-001, in healthy volunteers.

Fever Without an Apparent Source in Young Infants: A Multicenter Retrospective Evaluation of Adherence to the Dutch Guidelines.

Background: The Dutch fever without an apparent source (FWS) guidelines were published to timely recognize and treat serious infections. We determined the adherence to the Dutch FWS guidelines and the percentage of serious infections in infants younger than 3 months of age. Second, we identified which clinical criteria, diagnostic tests, and management were associated with nonadherence to the guidelines.

Dientamoeba fragilis in children: a systematic review on diagnostic considerations and efficacy of treatment.

: The presence of in feces is characterized by an asymptomatic carrier ship to a spectrum of gastrointestinal symptoms. However, a causal relationship remains to be elucidated. In this systematic review, we aimed to evaluate the relationship between the eradication of and symptoms to establish the strength of evidence that in symptomatic children warrants antibiotic treatment.

Pharmacokinetics of intravenous and inhaled salbutamol and tobramycin: An exploratory study to investigate the potential of exhaled breath condensate as a matrix for pharmacokinetic analysis.

Concentrations of drugs acting in the lungs are difficult to measure, resulting in relatively unknown local pharmacokinetics. The aim of this study is to assess the potential of exhaled breath condensate (EBC) as a matrix for pharmacokinetic analysis of inhaled and intravenous medication. A 4-way crossover study was conducted in 12 volunteers with tobramycin and salbutamol intravenously and via inhalation.

Risk of alanine transferase (ALT) elevation in patients with rheumatoid arthritis treated with methotrexate in a DAS-steered strategy.

Objective: To determine incidence of increased levels of alanine transferase (ALT) >2× upper limit of normal (ULN) in patients receiving methotrexate (MTX), treated according to a dynamic strategy, and to identify predictors of ALT of >2× ULN.

Methods: Data of 508 recent-onset rheumatoid arthritis (RA) patients from the BeSt study, randomized to initial monotherapy or combination therapy, were used. Treatment was dynamic, aiming at a disease activity score = ≤ 2.

'Insights in the relationship of joint space narrowing versus erosive joint damage and physical functioning of patients with RA'.

Objective: To evaluate the contribution of joint space narrowing (JSN) and erosions in general and in four different joint groups in relation to physical disability in rheumatoid arthritis (RA).

Methods: 5-year follow-up data from the Behandel Strategieën (BeSt) trial were used, where 508 patients with recent onset RA were treated aiming at a disease activity score≤2.4.

The association of treatment response and joint damage with ACPA-status in recent-onset RA: a subanalysis of the 8-year follow-up of the BeSt study.

Objective: Anticitrullinated protein antibodies (ACPAs) are suggested to identify different subsets of patients with rheumatoid arthritis (RA). The authors compared the clinical and radiological responses to Disease Activity Score (DAS)-steered treatment in patients with RA positive or RA negative for ACPA.

Methods: In the BehandelStrategieën (BeSt) study, 508 patients with recent-onset RA were randomised to four treatment strategies aimed at a DAS ≤2.

Towards personalized treatment: predictors of short-term HAQ response in recent-onset active rheumatoid arthritis are different from predictors of rapid radiological progression.

Objective: Personalized treatment depends on the treatment goals. Current prediction models to guide initial treatment choices focus on radiological damage progression. However, for some patients this outcome is less relevant, whereas short-term functional ability is relevant to all.

Association with joint damage and physical functioning of nine composite indices and the 2011 ACR/EULAR remission criteria in rheumatoid arthritis.

Objective: To compare nine disease activity indices and the new American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) remission criteria in rheumatoid arthritis (RA) and to relate these to physical function and joint damage progression.

Methods: Five-year data from the BeSt study were used, a randomised clinical trial comparing four treatment strategies in 508 patients with recent-onset RA. Every three months disease activity was assessed with nine indices (Disease Activity Score (DAS), DAS-C reactive proteine (DAS-CRP), Disease Activity Score in 28 joints (DAS-28), DAS28-CRP, Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI) and three DAS versions with adjusted tender joint scores) and categorized into remission, low, moderate and high disease activity (LDA, MDA, HDA).