Secukinumab demonstrates superiority over narrow-band ultraviolet B phototherapy in new-onset moderate to severe plaque psoriasis patients: Week 52 results from the STEPIn study.

BACKGROUND: Biologic treatments have been studied mainly in patients with a long-term history of psoriasis and previous treatment failures. OBJECTIVES: The purpose of this primary analysis of the STEPIn study is to determine whether early intervention with secukinumab in patients with new-onset moderate to severe plaque psoriasis is superior to standard of care treatment with narrow band ultraviolet B (nb-UVB) phototherapy. METHODS: The STEPIn study is a randomized, open-label, multicentre study to investigate early intervention with 52 weeks of secukinumab 300 mg administered subcutaneously versus standard treatment with nb-UVB phototherapy in patients with new-onset (≤12 months) moderate to severe plaque psoriasis (NCT03020199). The primary and additional secondary endpoints were ≥90% improvement in Psoriasis Area and Severity Index (PASI 90) at Week 52 and Investigator's Global Assessment (IGA mod 2011) 0/1 response at Week 52, respectively. RESULTS: In the secukinumab and nb-UVB study arms, 77/80 and 76/80 randomized patients received at least one dose of study treatment, respectively. The primary endpoint was achieved: 91.1% (70/77) of patients achieved a PASI 90 response at Week 52 in the secukinumab arm versus 42.3% (32/76) in the nb-UVB arm (p < 0.0001, odds ratio [OR] estimate [95% confidence intervals, CI] = 16.3 [5.6, 46.9]). The additional secondary endpoint was also achieved: 85.7% of patients achieved an IGA 0/1 response at Week 52 in the secukinumab arm versus 36.8% in the nb-UVB arm (p < 0.0001). The safety data were consistent with the safety profiles of secukinumab and nb-UVB with no new or unexpected safety signals. CONCLUSIONS: Secukinumab was superior to nb-UVB in treating patients with new-onset moderate to severe plaque psoriasis. The high and sustained skin clearance observed indicates that biologic treatment for psoriasis may be more effective if used early in the disease course.

Determination of Bovine Lactoferrin in Powdered Infant Formula and Adult Nutritionals by Heparin Affinity Extraction and Reverse-Phase High-Performance Liquid Chromatography/Ultraviolet Detection (HPLC/UV): Single-Laboratory Validation, First Action 2021.10.

BACKGROUND: Infant formulas, and pediatric and adult nutritional products, are being fortified with bovine lactoferrin (bLF) due to its beneficial impacts on immune development and gut health. Lactoferrin supplementation into these products requires an analytical method to accurately quantify the concentrations of bLF to meet global regulatory and quality standards. OBJECTIVE: To develop and validate a lactoferrin method capable of meeting the AOAC INTERNATIONAL Standard Method Performance Requirements (SMPR®) 2020.005. METHODS: Powder formula samples are extracted using warm dibasic phosphate buffer, pH 8, then centrifuged at 4°C to remove insoluble proteins, fat, and other solids. The soluble fraction is further purified on a HiTrap heparin solid-phase extraction (SPE) column to isolate bLF from interferences. Samples are filtered, then analyzed by LC-UV using a protein BEH C4 analytical column and quantitated using an external calibrant. RESULTS: The LOQ (2 mg/100 g), repeatability (RSD: 2.0-4.8%), recovery (92.1-97.7%), and analytical range (4-193 mg/100 g) all meet the method requirements as stated in SMPR 2020.005 for lactoferrin. CONCLUSION: The reported single-laboratory validation (SLV) results demonstrate the ability of this lactoferrin method to meet or exceed the method performance requirements to measure soluble, intact, non-denatured bLF in infant and adult nutritional powder formulas. HIGHLIGHTS: The use of a heparin affinity column to isolate lactoferrin from bovine milk products combined with a selective analytical chromatographic column provides suitable analyte specificity without requiring proprietary equipment or reagents.

Eltrombopag in patients with chronic immune thrombocytopenia in Asia-Pacific, the Middle East, and Turkey: final analysis of CITE.

CITE was a prospective, noninterventional study in adult patients with chronic immune thrombocytopenia treated with eltrombopag under routine clinical care in Asia-Pacific, the Middle East, and Turkey. Data to assess eltrombopag usage, compliance, and outcomes were collected from May 2017 to December 2020. Platelet response was defined as platelet count ≥50 × 103/µL in the absence of rescue medications and splenectomy. Quality of life was evaluated using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire. Noncompliance was defined as the number of missed doses and number of days where the patient did not follow food instructions. A total of 231 patients were enrolled; the median (range) duration of eltrombopag treatment was 484.5 (1-642) days. Compliance to prescribed eltrombopag dose since the previous routine visit was high at ≥96.0%. Baseline median platelet count was 19.0 × 103/µL, which increased to ≥50 × 103/µL at month 2 and mostly fluctuated between 70 × 103/µL and 100 × 103/µL thereafter. The median time to first platelet response was 1.05 (95% confidence interval: 0.92-1.28) months, and the median (interquartile range) maximum duration of platelet response was 193 (57-456) days. FACIT-F scores improved from a mean (standard deviation) 34.4 (12.1) at baseline to 38.5 (9.1) at month 18. Adverse events occurred in 50.9% of patients (n = 116), the most common being upper respiratory tract infection (8.3%) and headache (6.6%). These findings confirmed the effectiveness of eltrombopag treatment in routine practice and reassured that real-world compliance to eltrombopag-prescribed doses and dietary instructions in Asia-Pacific, the Middle East, and Turkey were in line with current recommendations.

Clinical efficacy and safety of secukinumab in patients with psoriasis and comorbidities: pooled analysis of 4 phase 3 clinical trials.

BACKGROUND: The influence of comorbidities on the efficacy and safety of biologic therapies in psoriasis has not been rigorously explored. OBJECTIVE: To assess the incremental burden of comorbidities on clinical efficacy and safety of secukinumab vs. etanercept and placebo among patients with plaque psoriasis pooled from 4 phase 3 trials. METHODS: Efficacy was assessed at week 12 according to achievement of Psoriasis Area and Severity Index (PASI) and Investigator's Global Assessment (IGA; modified 2011) responses. Efficacy comparisons between treatment arms stratified by comorbidity status were made using logistic regression analysis with nonresponder imputation. Relationships between baseline characteristics and clinical responses were evaluated by χ2 tests. RESULTS: Of 2401 patients, 1469 (61.2%) had ≥1 active baseline comorbidity. Regardless of comorbidity status, patients receiving secukinumab were more likely to achieve PASI and IGA responses than those receiving etanercept or placebo at week 12 (p < .05 for all comparisons). Body weight of ≥90 kg was consistently associated with a decreased likelihood of achieving PASI and IGA responses (p < .01 for all comparisons). Safety was comparable across treatment arms stratified by comorbidity. CONCLUSIONS: Secukinumab improved clinical outcomes and was well tolerated in patients with concomitant baseline comorbid conditions.

Impact of Secukinumab on Endothelial Dysfunction and Other Cardiovascular Disease Parameters in Psoriasis Patients over 52 Weeks.

Psoriasis increases the risk of cardiovascular (CV) disease. Secukinumab, a fully human monoclonal antibody against IL-17A, shows significant efficacy in psoriasis, but effects on CV markers are unknown. CARIMA (Evaluation of Cardiovascular Risk Markers in Psoriasis Patients Treated with Secukinumab) was a 52-week, randomized, double-blind, placebo-controlled, exploratory trial in patients with moderate to severe plaque psoriasis without clinical CV disease. Patients were randomly assigned to receive 300 mg or 150 mg secukinumab until week 52 or to receive placebo until week 12 and then 300 mg or 150 mg secukinumab until week 52. The primary outcome was endothelial function measured by flow-mediated dilation (FMD). Baseline FMD was significantly lower in psoriasis patients than healthy volunteers (4.4 ± 3.9% vs. 6.1 ± 3.3%, P = 0.01). At week 12, baseline-adjusted mean FMD was numerically higher in patients receiving secukinumab versus those receiving placebo, but this difference (300-mg group, +1.2%; 150-mg group, +0.76%; P = 0.223 and P = 0.403 by analysis of covariance) did not reach significance. At week 52, FMD increased across groups. FMD was significantly higher than baseline in patients receiving the label dose of 300 mg secukinumab for 52 weeks (+2.1%, 95% confidence interval = 0.8-3.3; P = 0.0022). Other relevant CV markers were unchanged. CARIMA indicates that secukinumab might have a beneficial effect on CV risk by improving the endothelial function of patients with plaque psoriasis.

Dynamics of targeted microbubble adhesion under pulsatile compared with steady flow.

Hemodynamic flow variations at low fluid shear stress are thought to play a critical role in local atherosclerotic plaque initiation and development and to affect plaque instability. Targeted microbubbles are being developed as intravascular agents for identifying atherosclerotic lesions using ultrasound. How variations in local hydrodynamic flow influence the adhesiveness of targeted microbubbles is not well understood. We postulated that rates of targeted microbubble binding and accumulation differ when subjected to steady flow (SF) as compared with oscillatory or pulsatile flow (PF), because PF imposes non-uniform blood rheology and periodic acceleration and deceleration of blood velocity, when compared with SF. We assessed the binding rates of targeted microbubbles in seven randomly assigned PF and seven matched SF replicate runs at low (<1 Pa) and intermediate (≥1 and <2.5 Pa) wall shear stress (WSS) by drawing 4.8 × 10(6) microbubbles mL(-1) over streptavidin-coated substrates, immobilized within a parallel plate flow chamber at a calculated density of 81 binding sites µm(-2). Selective binding and accumulation of targeted microbubbles was recorded in a single field of view using real-time video microscopy. Microbubble accumulation was modeled to obtain flow-mediated microbubble binding kinetics (amplitude, A, and rate constant, k). PF elicited higher microbubble accumulation rates, in comparison to SF. The rates of microbubble accumulation differed significantly between PF and SF (p < 0.05) at intermediate WSS but not at low WSS (p > 0.05). The rate of microbubble accumulation decreased as WSS increased.

Systems biology of the functional and dysfunctional endothelium.

This review provides an overview of the effect of blood flow on endothelial cell (EC) signalling pathways, applying microarray technologies to cultured cells, and in vivo studies of normal and atherosclerotic animals. It is found that in cultured ECs, 5-10% of genes are up- or down-regulated in response to fluid flow, whereas only 3-6% of genes are regulated by varying levels of fluid flow. Of all genes, 90% are regulated by the steady part of fluid flow and 10% by pulsatile components. The associated gene profiles show high variability from experiment to experiment depending on experimental conditions, and importantly, the bioinformatical methods used to analyse the data. Despite this high variability, the current data sets can be summarized with the concept of endothelial priming. In this concept, fluid flows confer protection by an up-regulation of anti-atherogenic, anti-thrombotic, and anti-inflammatory gene signatures. Consequently, predilection sites of atherosclerosis, which are associated with low-shear stress, confer low protection for atherosclerosis and are, therefore, more sensitive to high cholesterol levels. Recent studies in intact non-atherosclerotic animals confirmed these in vitro studies, and suggest that a spatial component might be present. Despite the large variability, a few signalling pathways were consistently present in the majority of studies. These were the MAPK, the nuclear factor-κB, and the endothelial nitric oxide synthase-NO pathways.

Systems and synthetic biology of the vessel wall.

Atherosclerosis is intimately coupled to blood flow by the presence of predilection sites. The coupling is through mechanotransduction of endothelial cells and approximately 2000 gene are associated with this process. This paper describes a new platform to study and identify new signalling pathways in endothelial cells covering an atherosclerotic plaque. The identified networks are synthesized in primary cells to study their reaction to flow. This synthetic approach might lead to new insights and drug targets.