tbuckley/cabot-search huggingface dataset:
P18 Therapeutic inertia in the management of moderate to severe psoriasis: a systematic review of cross-sectional studies
Journal: British Journal of Dermatology (2024)

Abstract Therapeutic inertia (TI) is the inability of physicians to initiate a more aggressive treatment in patients who need it. It is more common among patients with chronic disease and may be secondary to physician-related factors, patient-related factors, or healthcare system-related factors. This study aims to explore the evidence behind TI in the management of moderate-to-severe psoriasis and to determine the factors that contribute to its occurrence. An extensive literature search was conducted systematically in Cochrane Library, Medline, Epistemonikos, Google Scholar, and HERDIN from their inception up to June 2023. Cross-sectional studies that looked into TI in moderate-to-severe psoriasis and discussed the factors that lead to its occurrence were included. The review was limited to peer-reviewed journals in English. Outcomes were presented as counts and percentages, and notable findings from each study were highlighted. Three thousand two hundred and fifty-six records were identified but only four studies met the inclusion criteria and were included in the analysis. Based on the available evidence, the prevalence of TI in psoriasis varies from 25.4 to 35.6%. The occurrence of TI in psoriasis is largely caused by physician-related factors (reluctance to escalate treatment due to lack of knowledge and experience) and patient-related factors (satisfaction with current treatment or refusal to change treatment due to psychological barriers). Healthcare system-related factors were not directly explored. TI significantly impacts patient-reported outcomes in moderate-to-severe psoriasis. Although consequences on disease severity, quality of life, and treatment adherence were not explicitly reported in previous studies, it is reasonable to infer that TI has negative implications. Considering the effects of TI on these outcomes, having a high prevalence translates to negative consequences in psoriatic disease management. A focus on the specific effects of TI on treatment outcomes in patients with moderate-to-severe psoriasis, including patient satisfaction and quality of life, would also be good to explore with primary research. The limited data on the prevalence of therapeutic inertia in the management of moderate-to-severe psoriasis highlights a potential area for further research. A more detailed investigation into physician-related, patient-related, and healthcare system-related factors needs to be conducted to better understand this phenomenon and provide better evidence on how it affects the treatment of patients with an incurable and often stigmatizing disease.
P47 Pregnancy outcomes in women exposed to guselkumab: review of cases reported to the manufacturer’s global safety database
Journal: British Journal of Dermatology (2024)

Abstract Data on the use of biologics during pregnancy are limited. Guselkumab, a human IgG1λ monoclonal antibody approved for the treatment of moderate-to-severe psoriasis (PsO) and active psoriatic arthritis (PsA), is in clinical development for the treatment of inflammatory bowel disease (IBD). As IgG1λ antibodies can cross the placental barrier, we assessed pregnancy outcomes in pregnant women exposed to guselkumab. Cumulative data from the Janssen Global Safety Database reported through 12 July 2023 were summarized descriptively for medically confirmed and unconfirmed pregnancies with maternal exposure to guselkumab &amp;lt;3 months before conception, during or after first trimester (T1 or T2/T3), or any time during confirmed pregnancy. Pregnancy outcomes included live births with/without congenital anomalies; spontaneous abortions; elective terminations, stillbirths, or unspecified abortions with/without fetal defects; fetal deaths; ectopic pregnancies; induced/missed abortions; or ongoing pregnancies having no reported outcome. Cumulative through 12 July 2023, 590 pregnancy events [including twins (2); triplets (1)] in 586 guselkumab-exposed women were reported prospectively (N = 505) or retrospectively (N = 85). In cases with indication reported, most were PsO [90.0% (371/412)]; others included PsA [2.2% (9/412)], both PsO and PsA [3.4% (14/412)], and IBD [1.5% (6/412)]. In cases with data on the timing of guselkumab exposure, 14.3% (27/189) had exposure before conception, 77.8% (147/189) during T1, 5.3% (10/189) during T2/T3, and 2.6% (5/189) any time during pregnancy. Mean guselkumab exposure duration before pregnancy in known cases (N = 158) was 385 days (median, 238; range = 0–1717 days). Mean maternal age (N = 349) was 32.0 years (median, 32 years; range = 19–56 years). Outcomes were reported for 30.2% (178/590) of pregnancy events, including live birth [63.5% (113/178)]; spontaneous abortion [22.5% (40/178)]; elective termination (no fetal defects or unknown) [6.7% (12/178)]; ectopic pregnancy [3.4% (6/178)]; induced abortion [1.1% (2/178)]; fetal death [1.1% (2/178)]; and 1 event each (0.6%) of elective termination with fetal defect, missed abortion, and unspecified abortion with fetal defects. In pregnancy cases with known outcomes, rates of live births, spontaneous and elective/induced abortions, and congenital anomalies in women exposed to guselkumab ≤3 months before/during pregnancy are consistent with rates reported for the US general population, suggesting no apparent impact of guselkumab on pregnancy outcomes. Despite incomplete data on pregnancy outcomes, maternal age statistics, concomitant medication use, other risk factors, and duration of guselkumab exposure, these findings represent the most robust analysis of maternal guselkumab-exposed pregnancy outcomes to date. Additional evidence is needed to increase our understanding of the effects of guselkumab exposure on pregnancy outcomes across disease indications.
P58 Biosimilars: enhancing treatment accessibility for patients with psoriasis
Journal: British Journal of Dermatology (2024)

Abstract Psoriasis is a systemic inflammatory disease for which biological therapy can be life- transforming. In Chile, access to these treatments is limited by their high cost, which must be covered by patients, as the Chilean health system does not reimburse them. Owing to their lower cost, biosimilars offer an effective alternative to improve access to targeted therapies. Hyrimoz® (an adalimumab biosimilar) was approved by the Chilean Public Health Institute in August 2020 for moderate-to-severe plaque psoriasis. The objective was to describe the characteristics of Chilean patients using Hyrimoz in real life and the treatment response. A multicentre observational study was conducted in four dermatology centres in Santiago. The clinical records of 46 patients with moderate-to-severe psoriasis who did not respond adequately to topical or classic systemic therapies were evaluated between January 2022 and May 2024, for whom Hyrimoz was indicated. Demographic and clinical data were collected. Disease severity was evaluated according to psoriasis area and severity index (PASI) at 0, 3, 6, 9, and 12 months after starting the medication. Efficacy was measured during this period with PASI-75, PASI-90, and PASI-absolute&amp;lt;3. Adverse events reported by the patients and dermatologists were recorded and analysed. Data were analysed using descriptive statistics; 65.2% of patients were men, with an average age of 40.38 ± 12.79 years (16–64 years), and the disease duration was 18.21 ± 9.18 years; 69.6% of patients had comorbidities, the most common being mood disorders and anxiety (12), hypertension (7), and dyslipidaemia (7). All patients received at least one medication prior to the start of Hyrimoz®. The initial PASI was 22.45 ± 10.97 (5.5–52), and the initial body surface area was 23.39 ± 13.13% (3–60%). PASI-75 at 3, 6, 9, and 12 months was 52.38, 88.57, 91.3, and 81.82% respectively. PASI-90 at 3, 6, 9, and 12 months was 40.48, 60, 73.9, and 81.82%. PASI-absolute&amp;lt;3 at 3, 6, 9, and 12 months was 42.85, 68.57, 78.26, and 72.72%. Twenty patients presented with adverse effects: injection site pain (n = 9), infections (n = 8), headache (3); 5 patients of treatment due to loss of efficacy (5/46), and 3 patients for economic reasons (3/46). According to the literature, the observed response in patients was similar to that expected. The introduction of biosimilars in Chile represents an effective alternative that allows economic access to biologics in more patients with moderate–to-severe psoriasis who cannot receive other targeted therapies because of the cost.
Progressive chromatin rewiring by ETO2::GLIS2 revealed in a human iPSC model of pediatric leukemia initiation
Authors: Fabien Boudia, Marie Baille, Loelia Babin, Zakia Aid, Elie Robert, Julie Riviere, Klaudia Galant, Verónica Alonso-Pérez, Laura Anselmi, Brahim Arkoun, Nassera Abermil, Christophe Marzac, Salvatore Nicola Bertuccio, Alexia Regnault de Premesnil, Cecile K. Lopez, Alexandre Eeckhoutte, Audrey Naimo, Betty Leite, Cyril Catelain, Christophe Metereau, Patrick Gonin, Nathalie Gaspar, Juerg Schwaller, Olivier A Bernard, Hana Raslova, Murielle Gaudry, Antonin Marchais, Hélène Lapillonne, Arnaud Petit, Francoise Pflumio, Marie-Laure Arcangeli, Erika Brunet, Thomas Mercher
Journal: Blood (2024)
P130 ORKA-001: a novel extended half-life monoclonal antibody targeting IL-23 with the potential to improve upon currently available therapies for psoriasis
Journal: British Journal of Dermatology (2024)

Abstract Introduction &amp; Objectives Interleukin 23 (IL-23) is a proinflammatory cytokine that helps to maintain and activate T-helper 17 (Th17) cells, the primary pathogenic cells in psoriasis. Antagonism of the p19 subunit of IL-23 (IL-23p19) has proven to have robust efficacy and a favourable safety profile in the treatment of psoriasis. ORKA-001 is a novel, extended half-life, humanized IgG1 monoclonal antibody that binds IL-23p19. ORKA-001 has been engineered to have optimized properties with the aim of delivering an enhanced clinical profile compared with current treatments for psoriasis. Materials &amp; Methods ORKA-001 was evaluated in multiple in vitro and ex vivo assays in comparison to two benchmark antibodies that target IL-23p19: risankizumab (RIS) and guselkumab (GUS). Binding affinity to IL-23 was determined by surface plasmon resonance (SPR). Antagonism of human IL-23 signalling was evaluated via assays measuring STAT3 activity in cell lines. Inhibition of IL-23-induced IL-17 secretion was assessed using in vitro cellular assays, including in human peripheral blood mononuclear cells (PBMC). Half-life extension was measured via pharmacokinetic (PK) analysis in cynomolgus monkeys dosed with a single bolus of ORKA-001. Results ORKA-001 binds specifically to human IL-23 with an affinity below 20 pM. It potently inhibits STAT3 activity in cell lines and IL-17 secretion in IL-23-stimulated human PBMC. IL-23 binding affinity and functional potencies for IL-23 antagonism are comparable to or better than those of RIS and GUS. The half-life of ORKA-001 is significantly extended in cynomolgus monkeys compared with both RIS and GUS. Based on allometric scaling of the clearance of ORKA-001 observed in this study, predictive simulations of ORKA-001 PK in humans suggest that subcutaneous maintenance dosing every 6–12 months could be achieved while maintaining high antibody exposures. Conclusion ORKA-001 exhibits high selectivity and affinity for IL-23 in vitro, potent inhibition of downstream cellular signalling ex vivo, and an extended half-life in non-human primates compared with RIS and GUS. Both affinity and antibody exposure have been shown to have a positive correlation with efficacy in psoriasis, and ORKA-001 has the potential to exceed RIS and GUS on both metrics while requiring significantly fewer doses per year. In total, these data provide preclinical evidence of ORKA-001’s clinical potential to improve upon currently available therapies for psoriasis. Clinical studies are warranted to demonstrate this potential.
P20 A case of erythrodermic psoriasis successfully treated with ixekizumab combined with low-dose methotrexate to ensure sustained clearance: a case report
Journal: British Journal of Dermatology (2024)

Abstract Erythrodermic psoriasis (EP) is a severe type of psoriasis that requires immediate and effective treatment. Although recommended as first-line treatment, systemic immunomodulators such as methotrexate and/or cyclosporine can sometimes be ineffective or undesirable, hence the use of biologics. However, in cases of refractory disease, biologics may be combined with methotrexate to boost efficacy and optimize outcomes without compromising safety and tolerability. A 16-year-old Filipino male was seen at a tertiary hospital for generalized erythema with scaling. He had chronic plaque psoriasis since age 11 and was previously treated with methotrexate 10 mg weekly, folic acid supplementation, and alternate courses of topical clobetasol and calcipotriol every 2 weeks until near remission was achieved. He was then lost to follow-up and never went through phototherapy. The patient was diagnosed with EP and was treated simultaneously with methotrexate at a maximum of 17.5 mg/week and cyclosporine at 2.75 mg/kg/day. After 6 months of continuous treatment with no reported adverse effects, the patient still exhibited minimal improvement. The patient was then started with ixekizumab 80 mg subcutaneous injections every 4 weeks in an off-label indication and dose for his age in the Philippines. The biologic was given alongside low-dose methotrexate at 7.5 mg/week; cyclosporine was discontinued. After 12 weeks of ixekizumab in combination with low-dose methotrexate, the patient achieved PASI75. The patient received his last dose of ixekizumab at Week 20 in combination with methotrexate of the same dose with good response at PASI100, achieving complete skin clearance. Since discontinuation of ixekizumab, the patient remains lesion-free with low-dose methotrexate at Week 32, with no reported adverse effects. In a resource-constrained setting such as the Philippines, payments for treatment are largely out-of-pocket. Government subsidies for effective but expensive treatments such as biologics are limited, forcing physicians to revert to a more affordable but not necessarily more effective treatment. Methotrexate has been found to have moderate to good efficacy in the treatment of psoriasis. Its acceptable safety profile and affordable cost make it a favourable treatment option for patients with psoriasis in the Philippines. Due to its nature of being a slow starter, the concomitant use of low-dose methotrexate for at least 12 weeks provides a treatment reserve that will allow continuous efficacy once the biologic drug is discontinued. This case illustrates the effective and safe use of ixekizumab combined with methotrexate in the treatment of EP, a strategy employed to overcome limitations in management secondary to finances in a resource-constrained setting such as the Philippines.
P55 Additive regulatory effects of 1,25(OH)2D3 with anti-TNF and anti-IL-17A therapies in an <i>ex vivo</i> Th17-driven psoriatic arthritis synovitis model
Journal: British Journal of Dermatology (2024)

Abstract Psoriatic arthritis (PsA) is an inflammatory disorder associated with psoriasis (PsO) and is part of the broader spectrum of psoriatic diseases. Persistent psoriatic synovitis causes joint pain, structural damage, and various systemic manifestations. Th17 cells, central to PsA pathogenesis, secrete pro-inflammatory cytokines (such as IL-17A, IL-22, IFN-γ and TNF-α) and interact with immune and stromal cells, notably synovial fibroblasts. When activated, synovial fibroblasts produce a broad range of pro-inflammatory cytokines (e.g. IL-6 and IL-8), matrix metalloproteinases (MMPs), and RANKL, facilitating immune response persistence, tissue destruction, and bone erosion. Understanding PsA pathogenesis has led to biological treatments targeting key pro-inflammatory cytokines, particularly TNFα and IL-17A. However, many patients experience suboptimal efficacy or treatment discontinuation. Additionally, vitamin D deficiency is prevalent among PsA patients, with low serum 25(OH)D levels (&amp;lt;20 ng/mL) linked to higher anti-TNF treatment discontinuation risk.1 We hypothesized that 1,25(OH)2D3 could provide additional value to cytokine-targeting therapies in PsA. CCR6+ CD25−/low memory Th17 cells were sorted from peripheral blood mononuclear cells of healthy donors and co-cultured with synovial fibroblasts derived from PsA patients for 3 days, with or without adalimumab (anti-TNFα antibody), secukinumab (anti-IL-17A antibody), or 1,25(OH)2D3. Immunoassays evaluated treatment efficacy. CCR6+ CD25−/low memory Th17 cells and PsA fibroblasts formed a pro-inflammatory feedback loop, significantly promoting pro-inflammatory niche development in the ex vivo synovitis model. Our results showed that blocking TNFα and/or IL-17A suppressed fibroblast activation, decreasing IL-6, IL-8, and MMPs. However, neither single nor dual inhibition of TNFα and IL-17A adequately regulated IFN-γ and IL-22 levels in the synovitis model. Individual 1,25(OH)2D3 treatment broadly suppressed pro-inflammatory cytokines and fibroblast activation, particularly IL-17A and IL-22, but not TNFα. When combined with biologics, 1,25(OH)2D3 demonstrated additive regulatory effects, comprehensively modulating major pro-inflammatory cytokines such as TNFα, IL-17A, IFN-γ and IL-22. Additional inhibition of fibroblast activation was observed for IL-6, IL-8 and MMPs. Moreover, 1,25(OH)2D3 boosted anti-inflammatory cytokine IL-10 production, providing a regulatory advantage in PsA treatment. To conclude, 1,25(OH)2D3 provided a comprehensive regulatory effect on Th17-induced synovitis, presenting a promising therapeutic strategy to improve PsA anti-cytokine therapy. Further research on supplementation, timing, dosage and outcome evaluation in both in vivo and clinical studies is needed.
P107 Generalized pustular psoriasis: consequences of tedious procurement of spesolimab in Germany
Journal: British Journal of Dermatology (2024)

Abstract Generalized pustular psoriasis (GPP) is a potentially life-threatening, autoinflammatory skin disease which is considered a rare and special variant of psoriasis. In limited disease, only local therapy may be applied, yet acute exacerbations and chronic remitting disease will demand systemic treatment. Various therapeutics like methotrexate, ciclosporin and corticosteroids as well as TNF-, IL23- and IL-17 blocking agents have been casuistically described or evaluated in small clinical studies, none of them being licenced so far by the FDA and EMA. Recently, the anti-IL-36 receptor antibody spesolimab was approved as a targeted treatment option for acute phases of GPP. However, the German Joint Federal Committee (Gemeinsamer Bundesausschuss) denied an additional benefit compared with systemic glucocorticoids, which is why the substance is not available in Germany anymore. Here, we report on a 47-year-old female patient who during the tedious application process for spesolimab had to be alternatively treated with long-term high-dose glucocorticoids resulting in a septic condition for several weeks and distinct Cushing’s disease. After final approval and drug delivery through an international pharmacy, she was successfully treated with spesolimab and could be tapered from systemic corticosteroids.
P75 Bimekizumab led to rapid and deep normalization of molecular signatures associated with psoriasis area and severity index sub-components and disease activity, preceding clinical skin clearance
Journal: British Journal of Dermatology (2024)

Abstract To better understand the complete and rapid effects of bimekizumab (BKZ) on psoriatic skin at both a molecular and clinical level, we assessed the three psoriasis area and severity index (PASI) sub-components (erythema, thickness and scaling) and their associated gene signatures. Analysis of these individual measures is important given they can be obscured in the overall weighted composite score and may contribute to its complexity, as well as some inter-observer variability. Gene sets linked with PASI sub-components and disease activity were curated using public gene ontologies and refined based on genes found to be dysregulated in psoriasis. The dysregulation of these psoriasis-specific, PASI sub-component gene sets and their normalization post-BKZ treatment was assessed using bulk RNA-seq data from a Phase 2a trial.1 The rapid and durable effects of BKZ on the PASI sub-scores were evaluated in BE RADIANT, a Phase 3b trial.2 After two 320 mg doses, by Week 8 of BE RADIANT, BKZ-randomized patients achieved mean reductions of 89.0, 92.1 and 93.3% from baseline in erythema, thickness and scaling sub-scores, respectively. By Week 12, all three sub-components showed ≥95% mean improvement, which was maintained to Year 1 (Week 48), indicating clinical predictivity for sustainable skin clearance as early as Week 12. At the molecular level, bulk RNA-seq data from the Phase 2a trial showed complete normalization (to non-lesional levels and beyond; median % improvement 95.7–105.3%) of the gene sets associated with the PASI sub-components and disease activity by Week 8, after two doses. Furthermore, dysregulation of selected markers associated with erythema (CXCL8), thickness (KRT16) and scaling (LORICRIN) was observed in lesional psoriatic tissue (confirmed by RNAscope imaging) and normalized post-BKZ treatment. A correlation between baseline changes in interleukin (IL)17A/IL17F expression levels and mean gene expression changes in each curated gene set was identified (R = 0.36–0.60, FDR &amp;lt; 0.05), consistent with the known direct effect of IL17 on keratinocytes. BKZ treatment resulted in significant improvement of all PASI sub-scores by Week 12 and led to fast and deep normalization of the molecular signatures associated with these sub-components by Week 8. These findings show that clinically apparent skin clearance is preceded by molecular disease resolution. All three sub-components were equally normalized post-BKZ treatment, indicating each is reliable in evaluating clinical response to BKZ.