Exposure-response relationship of guselkumab and the potential of serum proteomics in identifying predictive biomarker candidates in psoriasis.

BACKGROUND: Response to biologics in psoriasis varies in real-world settings. Serum biomarkers could aid biologic selection and dose modifications to improve patient outcomes while encouraging cost-effective care. OBJECTIVES: To explore the exposure-response relationship for guselkumab (GUS), to define a GUS concentration target for optimal response and to evaluate the potential of serum protein levels as predictive biomarker candidates. METHODS: This is a prospective, multicentric, cohort study in psoriasis patients treated with GUS. Serum GUS trough concentrations (TCs) collected at multiple timepoints were measured using an in-house immunoassay. Next, proximity extension assay technology (Target 96 Inflammation Panel Olink®) was used to measure serum protein levels in a subcohort including 38 GUS patients (week 0 and week 4), six psoriasis patients naive for systemic treatment and four healthy controls. RESULTS: Seventy-five patients participated and 400 samples were collected. Guselkumab TCs and clinical response were correlated at week 4, week 12 and in steady-state (≥20 weeks). Optimal responders (Psoriasis Area and Severity Index [PASI] ≤ 2) had significantly higher TCs than suboptimal responders from week 4 onwards in treatment. An optimal steady-state TC of 1.6 µg/mL was defined. Although TC and absolute PASI were lower and worse, respectively, in patients weighing ≥90 kg, clinical outcomes referred to desirable to excellent PASI ranges. Therefore, we do not recommend systematically higher GUS doses in obese patients. We could not reveal early differentially expressed proteins to distinguish future optimal from suboptimal responders. CONCLUSIONS: We demonstrated an exposure-response relationship for GUS and an optimal steady-state TC of 1.6 µg/mL in real-world psoriasis patients. Hereby, we deliver more evidence that therapeutic drug monitoring poses a promising strategy in optimizing GUS treatment. No biomarker candidates were identified through serum proteomics. We propose protein screening should be repeated in larger cohorts to continue the quest for predictive biomarkers.

Discrepancies between ePrescriptions and dispensing in Belgium, 6 years after the launch of the electronic prescribing - a mixed-method study.

OBJECTIVES: The number of electronic prescriptions (ePrescriptions) grows steadily in Belgium as in other European countries. In the future, Belgium wants to dematerialize the ePrescription flow, removing all paper trails. A quality check of the digital content and implementation of national ePrescription guidelines in the field was conducted, comparing the content at both prescription and pharmacy side. METHODS: An explanatory mixed-methods design was applied. In a first phase, potential problems (warning flags) were identified by consulting stakeholders. Secondly, the warning flags were validated to problems (errors) in a random set of ePrescriptions collected in April 2019. In a third phase, explanatory interviews were held with various stakeholders in order to find explanations and to identify the initiators of these errors. RESULTS: In the first phase, 15 warning flags were identified to evaluate the quality of an ePrescription. In the second phase, a random selection of 11,798 ePrescriptions was validated. The most prevalent errors found, were the digital construction of the messages (18.88%), combined with lots of necessarily deemed substitutions by the pharmacist (3.39%) not following what was prescribed originally. In the third phase, stakeholders indicated that software of the prescriber and the use of inconsistent databases between prescriber and pharmacy can often be seen as the cause and initiator of these problems. CONCLUSIONS: Use of authentic medication databases and well-designed software systems have the potential to solve ePrescription problems. Focus should go to prevention instead of detection.

Monocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity.

Epidemiological and clinical reports indicate that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To elucidate the immunopathology underlying COVID-19 severity, we perform cytokine and multiplex immune profiling in COVID-19 patients. We show that hypercytokinemia in COVID-19 differs from the interferon-gamma-driven cytokine storm in macrophage activation syndrome, and is more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling shows that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Antigen presenting machinery expression is also reduced in critical disease. Furthermore, we report that neutrophils contribute to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together our findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity.

Anti-infliximab antibody concentrations can guide treatment intensification in patients with Crohn's disease who lose clinical response.

BACKGROUND: The presence of antibodies towards infliximab (ATI) is associated with lower infliximab (IFX) trough concentrations and loss of response. IFX treatment intensification is effective for restoring response in most, but not all patients with Crohn's disease (CD). AIM: To compare outcome, pharmacokinetics and immunogenicity of treatment intensification strategies in patients with CD who lost clinical response to IFX. METHODS: A retrospective cohort study was conducted, including 103 patients with CD who lost clinical response during IFX maintenance therapy and therefore received a double dose IFX (10 mg/kg) and/or a next infusion after a shortened interval. IFX and ATI concentrations were measured in consecutive trough samples, just before (T0) and after (T+1) treatment intensification. RESULTS: Clinical response (physicians' global assessment) and biological response and remission (CRP) were restored in 63%, 42% and 24% of patients (evaluated at T+1). Treatment intensification increased IFX trough concentrations from 1.2 µg/mL [0.3-3.6] at T0 to 3.6 µg/mL [0.5-10.2] at T+1 (P < .0001). Using a drug tolerant assay, ATI were detected in the T0 sample of 47% of patients. ATI negatively impacted the achieved IFX trough concentration (Spearman r -0.57, P < .0001) and the probability of clinical response (P = 0.034) at T+1. When ATI were quantifiable but <282 ng/mL eq. at T0, combined interval shortening and dose doubling was more effective for restoring therapeutic IFX trough concentrations (≥3 µg/mL at T+1) than dose doubling alone, which in turn was more effective than interval shortening alone (P < .001). CONCLUSION: Antibodies towards infliximab can guide clinical decision-making on treatment intensification.

Rapid clinical assessment of kidney function based on arm muscle circumference and serum creatinine.

A midarm muscle circumference (AMC) < 10th percentile indicates severe protein-energy malnutrition. We identified 20 consecutive patients receiving specialized nutritional therapy from the Nutrition Support Service of the New England Deaconess Hospital during a 3-mo period who had AMC < 10th percentile and 24-h urine and serum creatinine determinations performed. Mean weight was 96 +/- 25% of ideal body weight (IBW), with only 7 patients < 85% IBW, reaffirming that weight is often insensitive for the identification of lean tissue loss. Twenty-four-hour urine creatinine excretion confirmed most to be severely lean body mass depleted (creatinine-height index < 60% in 17 subjects) as predicted by AMC. Sixteen patients had normal kidney function as assessed by serum creatinine levels and hospital norms (0.3-1.2 mg/dl). However, abnormal creatinine clearances were found in 15 of 20 subjects (normal 80-100 ml/min), with a mean value (53 +/- 23 ml/min) also below normal. These results suggest that the usual normal range for serum creatinine, based on well-nourished patients, should be adjusted in severely malnourished patients. Considering the upper limit of normal serum creatinine in this population to be 0.7 mg/dl, to reflect the approximately 60% reduction in lean tissue indicated by an AMC < or = 10th percentile, would identify all but 1 patient with an abnormal creatinine clearance (sensitivity 93%, specificity 67%). Use of a predictive formula (the Cockcroft-Gault equation) also identified those with kidney dysfunction but overestimated actual function to a level not usually requiring drug dose adjustment and did not obviate the need for further testing.(ABSTRACT TRUNCATED AT 250 WORDS)