tbuckley/cabot-search huggingface dataset:
FC10 Dysregulation of the SPRY1-DGAT axis alters glyceride metabolism and promotes psoriasis
Journal: British Journal of Dermatology (2024)

Abstract Lipids play a crucial role in maintaining skin health. Previous studies have indicated that lipid disorders in psoriasis involve not only systemic dyslipidaemia but also alterations in lipid metabolites within skin tissue. Our study aims to investigate the impact of SPRY1-DGAT axis dysregulation on lipid metabolism in psoriasis, focusing on the role of glycerides, which have been less explored compared with phospholipids, fatty acids, and ceramides. Skin samples from healthy individuals and psoriasis patients were collected to measure the levels of DGAT (Diacylglycerol O-Acyltransferase) and glycerides. Primary cultured keratinocytes were used to assess glyceride content, proliferation, and differentiation. Additionally, we utilized SPRY1 (Sprouty1) overexpression in vitro and SPRY1 knockout (KO) transgenic mice models to observe phenotypic changes and metabolic alterations. The glyceride levels were quantified using lipidomic analyses, while DGAT expression was evaluated via immunofluorescence and Western blotting. Keratinocyte proliferation and differentiation were assessed through cell cycle analysis and marker expression studies. Cytokine secretion was measured using ELISA. Our results demonstrate that psoriasis patients exhibit significant abnormalities in glyceride metabolism, characterized by a notable decrease in the enzyme DGAT in their skin tissues. Our previous studies have indicated a close association between SPRY1 and psoriasis. In SPRY1 KO mice, we observed psoriasis-like phenotypes, including epidermal hyperplasia and inflammation, alongside similar glyceride metabolic abnormalities and reduced DGAT levels. The SPRY1-DGAT pathway was found to have a significant influence on glyceride metabolism, affecting keratinocyte proliferation, differentiation, and the secretion of inflammatory cytokines. Specifically, the downregulation of DGAT in psoriasis patients and SPRY1 KO mice correlated with increased keratinocyte proliferation and aberrant differentiation, contributing to the inflammatory environment characteristic of psoriasis. Metabolic abnormalities in psoriasis involve both systemic dyslipidaemia and localized changes within skin tissue. The downregulation of Spry1 and DGAT is intricately associated with abnormal glyceride metabolism in keratinocytes, leading to altered cell proliferation, differentiation, and inflammatory pathways. Our study highlights the importance of the SPRY1-DGAT axis in maintaining normal lipid metabolism and suggests that its dysregulation may play a critical role in the pathogenesis of psoriasis. Therapeutic strategies aimed at restoring normal glyceride metabolism through modulation of the SPRY1-DGAT pathway could potentially ameliorate psoriasis symptoms and improve skin health.
P19 The association between psoriatic disease severity and adherence to the Mediterranean diet: a systematic review of observational studies
Journal: British Journal of Dermatology (2024)

Abstract Psoriasis is a chronic inflammatory disease characterized by relapses and remission with no cure, and the Mediterranean diet has been most recommended due to its anti-inflammatory nature. This study aims to summarize the evidence behind the role of a Mediterranean diet in psoriasis and to determine the association between its adherence with psoriatic disease severity. A systematic search was conducted in PubMed, Cochrane Library, Epistemonikos, Google Scholar, and HERDIN from their time of inception up to November 2023. Observational studies that reported data on adherence to a Mediterranean diet and how it affects the severity of cutaneous psoriasis and/or psoriatic arthritis were included in the study. The review was limited to peer-reviewed journals written in the English language. Outcome measures were presented as counts and percentages. Eighteen records were identified but only six studies were included in the final analysis. Due to the diversity and inconsistency in methodology, a meta-analysis was not suitable for this systematic review. Our systematic review evaluated six observational studies from Italy, Greece, Spain, and France, each aimed at exploring the relationship between psoriatic disease severity and adherence to the Mediterranean diet in adult populations. These studies mainly adopted a cross-sectional observational design, encompassing individuals with mild-to-severe psoriasis. While these studies shared a common design, they varied in focus and measurement scales. However, the consistent trend observed across all studies suggests a potential association between adherence to a Mediterranean diet and reduced psoriasis severity. Despite this, the certainty of evidence based on the GRADE assessment is low due to the studies’ observational nature (risk of bias), clinical heterogeneity, indirectness, and lack of precision to establish definite evidence. Patients with psoriasis often inquire about the Mediterranean diet and how it can help improve their condition in daily clinical practice. Whilst the National Psoriasis Foundation admits to the limited data on the relationship between dietary patterns and psoriasis, it has still weakly recommended that patients with psoriasis consider ‘trying’ a Mediterranean diet based on low-quality evidence. Despite the low-quality evidence, there is potential in further exploring its benefits through properly conducted randomized controlled trials that look into its ability to improve not just the psoriatic disease but overall health.
P33 The impact of body mass index on psoriasis area and severity index response in patients treated with adalimumab
Journal: British Journal of Dermatology (2024)

Abstract Obesity and psoriasis are bidirectionally linked. Some biologics are given in higher doses in patients &amp;gt;90 kg while others have only one licensed dose. The bioavailability of subcutaneous medication is negatively impacted by fat volume with body mass index (BMI) a potential negative effector on treatment response. Our aim was to assess the impact of baseline BMI on psoriasis area and severity index (PASI) 75 response with adalimumab treatment. Patients recruited to BADBIR with complete datasets in our centre were included. Information was collected from BADBIR records and local electronic care records including age, gender, baseline BMI and PASI at baseline, 6 and 12 months. Statistical analysis was completed using Jamovi v2.0 (Sydney, Australia). We identified 46 patients including 33 males (71.7%) with a median age of 45.5 years [interquartile range (IQR) 35–51]. Most patients were overweight/obese (n = 38, 82.6%) with a median BMI of 29.1 kg/m2 (IQR 25.7–34.6). Disease severity was moderate-to-severe (n = 44, 95.7%) with a median PASI of 12.1 (IQR, 10.3–17.6). Using linear regression analysis, for every 1 standard deviation (SD) increase in baseline PASI, baseline BMI increased by 1.1 kg/m2. Conversely, for every 1 SD increase in baseline BMI, baseline PASI increased by 1.2. Using binomial regression, baseline BMI did not predict PASI75 response at Month 6 (P = 0.786) or Month 12 (P = 0.117). Data regarding the impact of BMI on treatment response in psoriasis are important to predict PASI response on an individualized patient basis. Studies have been conflicting with some suggesting higher weight in treatment-refractory patients and others identifying no difference. We have identified a reciprocal effect between PASI and BMI but fall short of identifying BMI as a predictor of PASI75 response. Large-scale studies including multiple biologic agents are required to further evaluate this.
FC16 Blood mass cytometry reveals Type 1 cytokine expression in blood of patients with paradoxical eczema secondary to biologics for psoriasis
Journal: British Journal of Dermatology (2024)

Abstract Biologics targeting the tumour necrosis factor (TNF) and interleukin (IL)-17/23 axis are effective treatments for psoriasis but can result in cutaneous adverse events. The pathogenesis of paradoxical eczema, a phenotype resembling atopic eczema occurring after biologic initiation for psoriasis, is unknown. This study aimed to explore the systemic disease signature of paradoxical eczema occurring in psoriasis patients treated with biologics. Peripheral blood mononuclear cells (PBMCs) from three patients with paradoxical eczema (two on adalimumab, one on guselkumab), six matched psoriasis controls receiving biologics and five healthy volunteers were subjected to staining for surface markers and eight intracellular cytokines: granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon alpha (IFNa), interferon gamma (IFNg), IL-4, IL-10, IL-13, IL-17a, TNF. Prior to staining, PBMCs from each donor were either stimulated with phorbol 12-myristate 13-acetate/ionomycin or left unstimulated. Mass cytometry was used to compare cell-type abundance and cell-type (cluster)-specific cytokine expression. After data cleaning, there were 8 613 686 live singlets which were clustered using FlowSOM and manually annotated based on canonical marker expression. There was lower abundance (false discovery rate adjusted P &amp;lt; 0.1) of the CD4 natural killer T (NKT) (logFC −5.17), CD8 NKT (logFC −4.16) and CD8 mucosal-associated invariant T (MAIT)/NKT (logFC −2.76) clusters in paradoxical eczema cases relative to psoriasis controls; the findings were similar for stimulated cells. Compared with healthy controls, cases had a lower abundance (adjusted P &amp;lt; 0.1) of the CD8 MAIT/NKT (logFC −4.17) and CD56dim NK (logFC −2.64) clusters. TNF expression was higher across most unstimulated cell clusters in cases than controls (36 out of 41 clusters), with 18 reaching statistical significance (adjusted P &amp;lt; 0.1) including CD4 T cells, CD8 T cells, gdT cells, B cells and NK cells. IFN-γ was more highly expressed in 21 case clusters encompassing CD4 T cells, CD8 T cells, gdT cells, B cells, monocytes and NK cells. In cases relative to controls, IFN-α was more highly expressed in the double-negative B (IgD− CD27−), Naive B, CD4 Naive, CD8 Naive and CD4+CD8+ Naive T-cell clusters; there was a lower expression in CD14 (classical) monocytes. There were few differences in GM-CSF, IL-4, IL-10, IL-13 and IL-17A expression between group clusters. On stimulation, there were no differences between case and control cytokine expression. These findings suggest that the systemic signature of paradoxical eczema is characterized by Type 1 inflammation and a reduced systemic cytolytic/NKT signature. Further work is required to establish the disease signature in skin and identify if Type 1 inflammation is the primary pathophysiological process in paradoxical eczema or a reactive phenomenon.
P114 Deucravacitinib treatment did not affect immune response to SARS-Cov-2 vaccines and infection in patients with plaque psoriasis: results from the Phase 3 POETYK long-term extension trial
Journal: British Journal of Dermatology (2024)

Abstract Introduction Deucravacitinib, an oral, selective, allosteric TYK2 inhibitor, is approved in the US, EU, and other countries for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy. Deucravacitinib was efficacious and well tolerated in the global, 52-week, Phase 3 POETYK PSO-1 (NCT03624127) and POETYK PSO-2 (NCT03611751) trials. Patients completing the parent trials could enrol in the ongoing, open-label POETYK long-term extension (LTE) (NCT04036435), which overlapped with the peak of the global COVID-19 (SARS-CoV-2) pandemic. We investigated serological responses and predictors of seroconversion to SARS-CoV-2 vaccination and/or infection during deucravacitinib treatment in the POETYK LTE. Methods POETYK LTE started in August 2019 and overlapped with the COVID-19 pandemic, which emerged in December 2019. The first infection in the POETYK program was reported 24 March 2020, the first vaccination occurred on 17 December 2020, and samples were collected through 2 August 2023. This analysis included patients who (i) were fully vaccinated with an mRNA vaccine or a non-mRNA vaccine or had a reported SARS-CoV-2 infection during the trial and (ii) had their first serum sample available ≥15 days after the second mRNA dose or ≥30 days and up to 229 days after a non-mRNA vaccine or infection. Spike RBD antibody level ≥0.8 U/mL and nucleocapsid antibody level ≥1.0 cut-off index were used as measures of seroconversion; nucleocapsid antibody levels ≥1.0 U/mL were used as an indicator of prior SARS-CoV-2 infection. Results 596 (87.8%) patients were vaccinated (mRNA vaccine, n = 498; non-mRNA vaccine, n = 98). Baseline characteristics were similar between patients who were vaccinated (n = 406), infected (n = 83), and both vaccinated and infected (n = 190). Seroconversion occurred in 99.2% of mRNA vaccine recipients and 98.9% of non-mRNA vaccine recipients [mean RBD antibody levels, 9085.1 and 4277.9 U/mL, respectively; range, 0.4–75 000 U/mL (seroconversion, ≥0.8 U/mL titre)]. Seroconversion occurred in 100% of infected unvaccinated patients (mean RBD antibody level, 3663.8 U/mL), 99.1% of noninfected vaccinated patients (6384.2 U/mL), and 100% of infected vaccinated patients (23 636.2 U/mL). The mean duration between reported infection and sample collection was 177 days. RBD antibody levels remained high for &amp;gt;24 weeks in mRNA vaccine recipients, regardless of the time after vaccination or infection. Age, body mass index, and sex were not predictors of antibody levels or seroconversion. Conclusions In the POETYK LTE trial, &amp;gt;98% of patients mounted a serologic response to SARS-CoV-2 vaccination and/or infection, with more robust responses in vaccinated than unvaccinated patients. Deucravacitinib did not impact immune responses to vaccines that protect against COVID-19.
P116 Real-world experience of bimekizumab for plaque psoriasis in adult patients with prior exposure to interleukin-17 inhibitors: a 52-week multicentre retrospective review
Journal: British Journal of Dermatology (2024)

Abstract For adult patients with plaque psoriasis, evidence remains sparse regarding switching within class from another interleukin-17 inhibitor (IL-17i) to bimekizumab. We conducted a real-world, multicentre retrospective study of bimekizumab use following prior IL-17i exposure. We identified 40 patients from 4 centres initiated on bimekizumab following prior IL-17i exposure. Effectiveness outcomes included Investigator Global Assessment (IGA), psoriasis area and severity index (PASI), body surface area (BSA), and IGA × BSA scores. Safety was assessed via treatment-related adverse events (AEs). Mean age was 44.5 (range: 18–62) years, with 52.5% (21/40) being female. Prior IL-17i agents included secukinumab (60%, 24/40), ixekizumab (42.5%, 17/40), and brodalumab (42.5%, 17/40); 37.5% (15/40) utilized ≥2 IL-17i agents. Reasons for prior IL-17i discontinuation included lack of efficacy (87.5%, 35/40), patient preference (5%, 2/40), psoriatic arthritis flare (5%, 2/40), and adverse event (AE; 2.5%, 1/40). Primary non-response to prior IL-17i was defined as lack of IGA 0/1 and/or 75% improvement in PASI (PASI75) response at Week 16, while secondary non-response to prior IL-17i was defined as loss of IGA 0/1 and/or PASI75 response at any point afterwards. At Weeks 52 ± 6: IGA 0/1 was achieved by 72.4% (21/29); mean PASI, BSA, and IGA × BSA improvements from baseline were 93.9% (9.9–1.0), 87.3% (9.5–1.0%), and 89.7% (26.1–2.6), respectively; 77.5% (31/40), 67.5% (27/40), and 60% (24/40) achieved PASI75, 90% improvement in PASI (PASI90), and 100% improvement in PASI (PASI100); 77.5% (31/40), 70% (28/40), and 60% (24/40) achieved absolute PASI scores &amp;lt;3, &amp;lt;2, and &amp;lt;1, respectively; and 70% (28/40) achieved BSA &amp;lt;1%. In prior IL-17i primary non-responders (n = 14), 57.1% (8/14) achieved IGA 0/1 and/or PASI90 and 50% (7/14) achieved PASI100 with bimekizumab treatment at Week 52 ± 6. In prior IL-17i secondary non-responders (n = 12), 66.7% (8/12) achieved IGA 0/1 and/or PASI90 and 41.7% (5/12) achieved PASI100 with bimekizumab treatment at Week 52 ± 6. Eleven AEs occurred (27.5%, 11/40), including candidiasis (10%, 4/40) and folliculitis (7.5%, 3/40). Five patients (12.5%) discontinued treatment [AEs: anxiety (n = 1); inflammatory bowel disease (n = 1); inefficacy (n = 2); pregnancy (n = 1)]. The BE RADIANT open-label extension study demonstrated IGA 0/1 (73.6%), PASI90 (73.6%), and PASI100 (47.2%) responses at Week 48 for secukinumab PASI90 non-responders switched to bimekizumab following a 48-week randomization period. Our real-world study at Week 52 ± 6 is comparable to these results. Notably, prior IL-17i primary non-responders and patients with multiple biologic failures were included in this analysis, but excluded from Phase III clinical trials. We highlight the long-term utility of bimekizumab for IL-17i-exposed patients. Study limitations include its small sample and retrospective nature.
P09 Characterizing the burden of generalized pustular psoriasis in the United Kingdom: insights from the SCRIPTOR study
Journal: British Journal of Dermatology (2024)

Abstract Generalized pustular psoriasis (GPP) is a heterogeneous, systemic, neutrophilic, inflammatory disease with chronic symptoms and periods of flaring that negatively impact a patient’s quality of life (QoL). The goal of the international, non-interventional SCRIPTOR study is to understand the clinical burden of GPP, including flare frequency, treatment patterns and healthcare resource utilization. Between December 2022 and May 2023, data were collected from five dermatology centres in the UK using medical charts of patients diagnosed with GPP (2011 onwards). Patients diagnosed with acute generalized exanthematous pustulosis without a history of GPP were not included. Twenty-seven patients (n = 18; 67% female), with a mean [standard deviation (SD)] age at GPP diagnosis of 53.1 (19.7) years (range: 18.0–86.0 years) were included. Most patients were Caucasian (n = 21; 78%), followed by Asian (n = 4; 15%) and mixed/unknown ethnicity (n = 2; 7%). Most patients (74%) had ≥1 GPP risk factor, the most common being a previous diagnosis of plaque psoriasis (plaque PsO; 65%), medication use (55%) and comorbidities (50%). Common comorbidities were plaque PsO (58%), hypertension (46%) and psychiatric conditions (29%). Diagnosis of GPP predominantly occurred in an inpatient setting (74%), with guideline diagnostic criteria used in ∼80% of cases. At GPP diagnosis, 95% of patients had pustules. Prior to diagnosis of GPP, seven patients (26%) had a flare. Among patients with a follow-up duration of ≥1 year (n = 13), mean (SD) flare episodes per year was 0.9 (0.6). GPP flare triggers (infections and medication use/withdrawal) were documented in six patients (43% of post-diagnosis cases). Physical examination and laboratory testing were commonly used in the assessment of GPP flares. Psoriasis area and severity index and dermatology life quality index were used in ∼30% of routine follow-ups and ∼20% of documented flare cases. At diagnosis, there were 17 all-cause (median/mean duration: 17.0/22.1 days) and 3 flare-related (27.0/29.0 days) hospitalizations documented. Post-diagnosis, 11 patients had ≥1 hospital/emergency room admission due to: GPP flare (n = 14, 74%), complications, comorbidity management and adverse events (n = 3, 16% each). The most prescribed medications for flare treatment (n = 39) were topical corticosteroids (n = 9), retinoids (n = 7), methotrexate and ciclosporin (n = 4 each). Methotrexate (n = 23), retinoids (n = 14) and ciclosporin (n = 8) were often prescribed for long-term treatment (n = 74). From pre-diagnosis onwards, GPP exerts a significant burden, with recurrent flare episodes, hospitalizations and complications. The use of guideline diagnostic criteria varies, and disease severity and QoL assessment tools are underutilized. There are different approaches used for the treatment of GPP flares and long-term treatment. Overall, these findings emphasize the need for continuous treatment and comprehensive guidelines for GPP in the UK.
P42 KLHDC7B participates in the mechanism of UVB treatment for psoriasis by regulating CHOP and the KEAP1/NRF2 pathway
Journal: British Journal of Dermatology (2024)

Abstract Objective UVB phototherapy is an important method for the treatment of psoriasis, but the specific mechanism is unclear. KLHDC7B is a Kelch domain-containing protein that has been widely noted involving in multiple important cellular processes, but its expression and function in psoriasis remain to be further elucidated. The objective of this study was to explore the levels of KLHDC7B in psoriasis lesions and psoriasis keratinocytes with UVB irradiation. In addition, this study aimed to investigate whether KLHDC7B participates in the UVB treatment in patients with psoriasis. Methods We used quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting to determine the levels of KLHDC7B. QRT-PCR and ELISA were used to detect the secretion levels of IL-1β, CCL20 and CXCL10. Cell apoptosis was analysed by flow cytometric method. QRT-PCR and Western blotting were used to detect the expression of CHOP and KEAP1/NRF2 pathway. The results were statistically analysed by t-test. Results Our study showed a high expression of KLHDC7B in psoriasis lesions and keratinocytes stimulated with M5 for the psoriasis model. After UVB treatment, KLHDC7B was further increased. Knockdown of KLHDC7B reversed UVB-induced apoptosis and levels of IL-1β, CCL20 and CXCL10. Overexpression of KLHDC7B can improve the endoplasmic reticulum stress marker protein CHOP expression and NRF2 level. KLHDC7B could induce CHOP-mediated apoptosis and activate the KEAP1/NRF2 pathway to alleviate inflammation. In addition, we found that UVB promoted KLHDC7B expression through the nearby LncRNA called LncKLHDC7B-2. Conclusion KLHDC7B may act as a disease suppressor and play a key role in UVB treatment for psoriasis, which may provide a new target for treatment.
P13 Real-world evidence of oral roflumilast in patients with moderate-to-severe psoriasis
Journal: British Journal of Dermatology (2024)

Abstract Background Oral roflumilast, a phosphodiesterase (PDE)-4 inhibitor, approved for chronic obstructive pulmonary lung disease, has been proposed as an affordable and effective off-label therapy in psoriasis. However, real-world data is sparse. Methods All patients with moderate-to-severe plaque-type psoriasis treated with oral roflumilast 500 µg once-daily between February 2021 and April 2024 at Department of Dermatology at Bispebjerg Hospital, Copenhagen Denmark were included. The main outcomes were absolute PASI4 at 3 months and drug retention at 12 months. Results A total of 65 patients received therapy. At baseline, median age was 43.6 years [interquartile range (IQR): 33.2–62.3], median psoriasis area and severity index (PASI) 6.5 (IQR 3.4–10.6), and 42 (65%) patients were biologic-naïve. Among all patients, PASI was available for 34 patients at 3 months, with absolute PASI4 achieved by 25 patients, corresponding to 74% (as observed) and 58% (modified as observed; i.e. discontinuations due to lack of effectiveness considered non-response), respectively. Of all patients with minimum 12 months follow-up, 17 (57%) were still in active treatment after 1 year. Among biologic-naïve patients, PASI4 after 3 months was achieved by 23 [79% (as observed)] and 23 (74%) (modified as observed). Of biologic-naïve patients with a minimum 12-month follow-up, 16 (89%) still received oral roflumilast after 1 year. Conclusions and relevance This real-world study highlights oral roflumilast as a viable treatment alternative for psoriasis, especially in biologic-naïve patients.