Successful tapering of dupilumab in patients with atopic dermatitis with low disease activity: a large pragmatic daily practice study from the BioDay registry

BACKGROUND: Limited data are available regarding patient-centred dosing of dupilumab for atopic dermatitis (AD) in daily practice. OBJECTIVES: To evaluate our patient-centred dupilumab dosing regimen in daily practice, to assess prognostic factors for successful tapering and to estimate medication-related cost savings. METHODS: This prospective multicentre study included adult patients with AD, participating in the BioDay registry, treated with dupilumab for ≥ 1.3 years. Interval prolongation was considered in the case of dupilumab standard dose for ≥ 1 year and persistent controlled AD [Eczema Area and Severity Index (EASI) ≤ 7; ≥ 6 months]. Primary endpoints were the mean EASI and Numeric Rating Scale (NRS)-pruritus after the start of tapering. Prognostic factors for successful tapering were analysed with logistic regression and a cost-savings analysis was performed. RESULTS: A total of 595 patients were included, of whom 401 patients [mean EASI 2.5 (SD 2.3); NRS-pruritus of 2.4 (SD 1.9) at the start of tapering] prolonged their dupilumab interval. In 83.3% of these patients tapering was successful; most patients used dupilumab every 3 or 4 weeks (Q3W/Q4W). A significant small increase was observed for EASI (highest mean 3.5) and NRS-pruritus (highest mean 3.2) (P < 0.001); however, scores remained low. Predicting successful tapering showed nonsignificant odds ratios for all incorporated variables. The estimated cost savings was €3 977 033.98 for 401 patients between January 2019 and June 2022. CONCLUSIONS: This study showed successful tapering of dupilumab in 83.3% of patients with AD who attempted tapering, while maintaining controlled disease and with the majority using Q3W/Q4W. Interval prolongation can be beneficial both for the patient and from a socio-economic perspective

Dupilumab provides sustained effectiveness on patient-reported outcomes and favorable safety in patients with moderate-to-severe atopic dermatitis: up to 5-year results from the daily practice BioDay Registry

Background: Long-term daily practice data on patient-reported benefits of dupilumab for atopic dermatitis (AD) remains limited. Objective: To evaluate patient-reported outcome measures (PROMs) and the safety of dupilumab in patients with moderate-to-severe AD over a follow-up period of up to 5 years. Methods: Data were extracted from the prospective, multicenter BioDay registry (October 2017–2022) of patients with moderate-to-severe AD treated with dupilumab in daily practice. Results: In total 1223 patients, 1108 adults and 115 pediatric patients were included. After ≥1 year of treatment, mean Patient-Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), Numeric rating scale (NRS)-pruritus ranged between 7.8 and 8.7, 3.5 and 4.2, and 2.9 and 3.1 in adults, respectively, whilst these patient-reported outcome measures (PROMs) ranged between 8.9 and 10.9, 4.4 and 6.4, and 3.0 and 3.7 in pediatric patients, respectively. At follow-up, overall work impairment decreased from 40.1% to 16.3% to 13.3% in adults. Furthermore, class I obesity and itch-dominant patients generally had less favorable treatment response. Of all patients, 66.8% reported ≥1 adverse event, with conjunctivitis being the most common (33.7%). Limitations: The overall percentage of missing values for selected PROMs was 26% in adults and 46% in pediatric patients. Conclusion: In addition to favorable safety, dupilumab has demonstrated sustained effectiveness across various PROMs, underscoring the treatment benefits from patients' perspectives

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Successful tapering of dupilumab in patients with atopic dermatitis with low disease activity:a large pragmatic daily practice study from the BioDay registry

BACKGROUND: Limited data is available regarding patient-centered dosing of dupilumab for atopic dermatitis (AD) in daily practice.OBJECTIVES: To evaluate our patient-centered dupilumab dosing regimen in daily practice, to assess prognostic factors for successful tapering and to estimate medication-related cost savings.METHODS: This prospective multicenter study included adult AD patients, participating in the BioDay registry, treated with dupilumab for ≥1.3 years. Interval prolongation was considered in case of dupilumab standard dose for ≥1 year and persistent controlled AD (Eczema Area and Severity Index (EASI)≤7); ≥six months). Primary endpoints were the mean EASI and Numeric Rating Scale (NRS)-pruritus after start of tapering. Prognostic factors for successful tapering were analyzed with logistic regression and a cost saving analysis was performed.RESULTS: A total of 595 patients were included, of which 401 patients (mean EASI 2.5 (SD 2.3)); NRS-pruritus of 2.4 (SD 1.9) at start tapering) prolonged dupilumab interval. In 83.3% of these patients tapering was successful; most patients used dupilumab every 3 or 4 weeks (Q3W/Q4W). A significant small increase was observed for EASI (highest mean 3.5) and NRS-pruritus (highest mean 3.2) (p&lt;0.0001), however scores remained low. Predicting successful tapering showed non-significant odds ratios for all incorporated variables. The estimated cost saving was 3,977,033.98 EUR for 401 patients between January 2019-June 2022.CONCLUSIONS: This study showed successful tapering of dupilumab in 83.3% of AD patients who attempted tapering while maintaining controlled disease and with the majority using Q3W/Q4W. Interval prolongation can be both beneficial for the patient and from a socio-economic perspective.</p

Nucleolar Integrity Is Required for the Maintenance of Long-Term Synaptic Plasticity

<div><p>Long-term memory (LTM) formation requires new protein synthesis and new gene expression. Based on our work in <i>Aplysia</i>, we hypothesized that the rRNA genes, stimulation-dependent targets of the enzyme Poly(ADP-ribose) polymerase-1 (PARP-1), are primary effectors of the activity-dependent changes in synaptic function that maintain synaptic plasticity and memory. Using electrophysiology, immunohistochemistry, pharmacology and molecular biology techniques, we show here, for the first time, that the maintenance of forskolin-induced late-phase long-term potentiation (L-LTP) in mouse hippocampal slices requires nucleolar integrity and the expression of new rRNAs. The activity-dependent upregulation of rRNA, as well as L-LTP expression, are poly(ADP-ribosyl)ation (PAR) dependent and accompanied by an increase in nuclear PARP-1 and Poly(ADP) ribose molecules (pADPr) after forskolin stimulation. The upregulation of PARP-1 and pADPr is regulated by Protein kinase A (PKA) and extracellular signal-regulated kinase (ERK)—two kinases strongly associated with long-term plasticity and learning and memory. Selective inhibition of RNA Polymerase I (Pol I), responsible for the synthesis of precursor rRNA, results in the segmentation of nucleoli, the exclusion of PARP-1 from functional nucleolar compartments and disrupted L-LTP maintenance. Taken as a whole, these results suggest that new rRNAs (28S, 18S, and 5.8S ribosomal components)—hence, new ribosomes and nucleoli integrity—are required for the maintenance of long-term synaptic plasticity. This provides a mechanistic link between stimulation-dependent gene expression and the new protein synthesis known to be required for memory consolidation.</p></div

PAR is required for Fsk-induced synthesis of new rRNAs.

<p>(A) Fsk treatment upregulates unedited precursor rRNA (ht rRNA) (black bar) 1.8 fold in hippocampal slices compared with untreated controls (white bar). This increase is prevented when PAR is blocked by 3-AB (grey bar). (B) The PARP-1 dependent immediate-early gene <i>c-jun</i>, was used as a positive control. Student's t-test; * = p<0.05; ** = p<0.01.</p

Forskolin-induced PARP-1 and pADPr increase requires PKA activity.

<p>Left column (A, C, E): Representative Western blots used for quantification shown in right column (B, D, F). Phosphorylation of the PKA pathway substrate S6K was used as a stimulation-dependent positive control quantified as the ratio of p-S6K to total S6K (A, B). Histone 2B was used as a loading control (C, E). Fsk treatment (black bar) produced an increase of p-S6K, PARP-1, and pADPr (B, D, and F, respectively). The Fsk induced upregulation of both PARP-1 and pADPr was prevented by the PKA inhibitor KT5720 (grey bar; B, D, F). The inhibitor alone had no effect on PARP-1 or pADPr levels (striped bar; D, F respectively) compared with basal controls (white bar; D, F). Student's t-test (B,D,F); * = p<0.05; ** = p<0.01; NS = not significant.</p

Forskolin-induced increase of PARP-1 and pADPr requires the ERK pathway.

<p>Left column (A, C, E): Representative Western blots used for quantification shown in right column (B, D, F). Phosphorylation of the ERK pathway substrate S6K was used as a stimulation-dependent positive control quantified as the ratio of p-S6K to total S6K (A, B). Histone 2B was used as a loading control (C, E). Fsk treatment (black bar) produced an increase of p-S6K, PARP-1, and pADPr (B, D, and F, respectively). The Fsk induced increase was prevented by the ERK inhibitor U0126 (grey bar; B, D, F). The inhibitor alone had no effect on PARP-1 or pADPr levels (striped bar; D, F respectively) compared with basal controls (white bar; D, F). Student's t-test (B,D,F); * = p<0.05; ** = p<0.01; NS = not significant.</p