tbuckley/cabot-search huggingface dataset:
P129 Inflammation and autoimmunity dynamics in psoriasis
Journal: British Journal of Dermatology (2024)

Abstract Psoriasis is a chronic, immune-mediated, inflammatory disorder that extends beyond the skin, and the concept of psoriatic disease emphasizes the systemic inflammation. Specific immunologic pathways responsible for the development of psoriasis have been discovered, but no certain biomarkers where directly associated with this entity. Psoriatic disease, antinuclear antibodies (ANA) and inflammation markers have been linked in different studies for assessment of disease course during biologic therapy. Our objective was to evaluate ANA profile and the evolution of inflammation markers among a subgroup of biological agent naive patients with moderate-to-severe plaque psoriasis at the moment of biologic therapy initiation and after 6 months of treatment. ANA, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and neutrophils-to-leukocytes rates (NLR) were analysed in the second Department of Dermatology, at Colentina Clinical Hospital in Bucharest. ELISA method was used for ANA levels, serum CRP levels were measured quantitatively with the immunoturbidimetric method, ESR was measured with the Westergreen method, and NLR was calculated using Fluorescence Flow Cytometry values of neutrophils and leukocytes. Our preliminary results indicate that, although inflammatory markers are present in a severity-dependent manner, there is no substantial evidence of autoimmune involvement. Further detailed findings will be presented in our paper, as the inclusion period for the study remains ongoing until the end of the month.
P69 Modelling epidermal melanocyte behaviour during plaque psoriasis progression and resolution
Journal: British Journal of Dermatology (2024)

Abstract Melanocytes in human epidermis reside in the basal layer in a ratio of 1 melanocyte to ∼10 keratinocytes. In healthy epidermis, melanocytes neither divide nor undergo apoptosis. In psoriasis, the 1:10 ratio is maintained despite significant keratinocyte hyperplasia, suggesting an increase in melanocyte numbers. We investigated whether melanocyte numbers change in active psoriasis plaques and after plaque resolution upon treatment with biologics, and via the impact of psoriasis-related cytokines on melanogenesis in primary normal melanocytes in vitro. Immunohistochemistry (IHC) with MITF (melanocyte marker) and Ki67 (proliferation marker) on lesional and non-lesional samples (n = 11) at baseline and after 12 weeks of treatment assessed melanocyte proliferation. Melanocyte number/mm of basal layer and melanocyte/keratinocyte ratio were estimated by analysis on ImageJ. The TUNEL-assay and IHC staining with pro-apoptotic marker, Cleaved Caspase 3, and anti-apoptotic marker, BCL-2 were performed on lesional and non-lesional samples (n = 5) at baseline and after 4 and 12 weeks of treatment to determine if melanocytes undergo apoptosis upon treatment with biologics. Primary normal human melanocytes were treated with proinflammatory cytokines (IL-17, TNF-α, IL-22, and IL-23) to assess their influence on melanogenesis via immunocytochemistry (ICC) and Western blot (WB) analysis. Proliferating melanocytes were detected in non-lesional and lesional samples and in resolving plaques after treatment but not in healthy control epidermis. Melanocyte number/mm of the basal layer was significantly higher in non-lesional compared with both lesional sections and healthy controls (P &amp;lt; 0.0001), suggesting melanocyte expansion occurs prior to psoriasis plaque establishment. Twelve weeks after treatment, melanocyte numbers in lesional and non-lesional samples were still significantly higher than controls (P &amp;lt; 0.05) despite the reduction in keratinocyte numbers. The TUNEL-assay and Cleaved Caspase 3 staining did not detect evidence of melanocyte apoptosis. ICC and WB analysis of treated primary melanocytes revealed that TNF-α decreases the activity of the rate-limiting melanogenesis enzyme tyrosinase and down-regulates TRP1 both when this cytokine was used alone and in combination with the other cytokines. This study shows early melanocyte dysregulation supporting a role for melanocytes in psoriasis pathogenesis perhaps via an ADAMSTL5-initiated inflammation. The higher melanocyte numbers are retained even after treatment, and we were unable to detect melanocyte deletion/apoptosis despite a reduction in keratinocyte number. We show the direct inhibitory impact of psoriasis-associated cytokines on melanogenesis. This raises intriguing questions as to the nature of melanocyte proliferation in this benign inflammatory skin disease and suggests that such ectopic melanocytic proliferation in the epidermis may not be a harbinger of malignancy risk.
P14 A multicentre, randomized, double-blind, placebo-controlled Phase II study to evaluate the efficacy and safety of individual dose regimens of HB0017 in patients with moderate-to-severe plaque psoriasis
Journal: British Journal of Dermatology (2024)

Abstract HB0017 is a recombinant humanized IgG1 monoclonal antibody that targets IL-17A. To investigate HB0017 optimal dosage and possible dosing interval during maintenance therapy to inform Phase III studies. A total of 81 patients with moderate-to-severe plaque psoriasis received HB0017 300 mg (n = 41) or placebo (n = 40) at Weeks 0, 1, 2, 4, and 8. From Week 12 to Week 28, patients in the HB0017 group were given HB0017 300 mg once every 8 weeks. And patients in the placebo group were given HB0017 300 mg at Week 12, 13, 14 and 16, and then every 4 weeks until Week 28. Efficacy, safety, pharmacokinetics, and immunogenicity were assessed in Week 36. After 12 weeks of treatment, HB0017 300 mg resulted in significantly higher PASI 90 and sPGA0/1 response rates vs. placebo (P &amp;lt; 0.001). At Week 12, in the HB0017 group, 69.4% of patients achieved PASI 90, increasing to 97.6% at Week 24, then maintained throughout the follow-up period. And 78.2% of patients achieved sPGA0/1, increased to comparable peak levels at Week 28(97.6%), then maintained to Week 36(97.5%). In the placebo group, 1.0% of patients achieved PASI 90 at Week 12, increased to 94.3% at Week 28, then maintained throughout the follow-up period. 1.1% of patients achieved sPGA0/1, increased to 91.2% at Week 24, then maintained to Week 36(91.4%). The overall safety profile of HB0017 was similar to those of similar drugs, and no new safety signals were identified. These data provide evidence to support the evaluation of HB0017 300 mg maintenance dosing both every 8 and every 4 weeks in Phase III clinical trials.
FC08 Characterization of plasmacytoid dendritic cells-targeted CAR-T cells from patients with immune-mediated inflammatory diseases
Journal: British Journal of Dermatology (2024)

Abstract Since the study by Mougiakakos et al., published in 2021 demonstrated the remission of a patient with systemic lupus erythematosus thanks to treatment with anti-CD19 CAR-T cells, (1) a growing number of studies have focused on autoimmune diseases (AID). Plasmacytoid dendritic cells (pDCs), which express highly the CD123 molecule, also play a major role in the pathophysiology of many types of AID. In psoriasis, pDCs secrete IFN-I intensively, leading to inflammation and recruitment of inflammatory cells to the skin, promoting Th17 polarization of LTs and phenotypic changes in keratinocytes. (2) Recently, our team has developed an anti-CD123 CAR-T targeting the pDCs in the context of AID. Our project aims to deeply characterize the phenotype and functional capacities of CD123 CAR-T using T cells from patients (psoriasis, hidradenitis suppurativa, systemic sclerosis and systemic lupus erythematosus) at different stages of the disease and treated with various biotherapies. T cells from patients or healthy donors (HD) were isolated from peripheral blood mononuclear cells and then activated and modified to express a third-generation CD123 CAR (CAR123). CAR-T proliferation, transduction efficiency and phenotype were assessed before (Day 0), after CAR insertion and at the end of in vivo culture (Day 10). The functionality of CAR-T was assessed through their cytotoxic activity and their ability to secrete cytokines in the presence of their target. The in vitro functional persistence of CAR-T is assessed using a model in which CAR-T are challenged with CD123+ cells every 3–4 days for 15 days. Transduction efficiency of the CAR123 is high in all patients (72.4% ± 18.9%, n = 28) and HD (70.4% ± 15.3%, n = 4) (P = ns). Patient-derived CAR123 effectively lysed autologous pDCs in vitro in a similar manner to HD (82.8% ± 14.2%, n = 28 for patients and 67.3% ± 10.7%, n = 4 for HD, P = ns). Importantly, CAR123 maintained their in vitro cytotoxic activity after 6 rechallenges with no difference with HD CAR123. Upon engagement with their target, CAR123 secreted Th1-type cytokines (IFN-γ and TNF-α) as HD CAR123. In the AID context, CAR-T are produced from potentially activated or autoreactive T cells from patients. Importantly, our preliminary results show the feasibility of the production and in vitro efficacy of CAR123 from patient T cells to a similar extend to CAR123 from HD. Further characterization of CAR-T phenotype and function is underway. In addition, in vivo experiments to demonstrate the value of CD123 CAR-T cells in these diseases are ongoing.
FC18 Par1 signalling between T cells and keratinocytes mediates Klk6-elicited skin inflammation in a ROCK2-independent manner
Journal: British Journal of Dermatology (2024)

Abstract Kallikrein 6 (KLK6) is highly elevated in lesional epidermis of human psoriasis, and keratinocyte (K5)-specific overexpression of Klk6 (Klk6+) in mice results in the spontaneous development of psoriasis-like skin lesions that are abrogated in the global absence of the protease-activated receptor (Par)1. PAR1, a G-protein coupled receptor, is expressed on keratinocytes (KCs) and T cells and can signal via phosphorylation of ROCK2. We tested the hypothesis that Klk6-Par1 signalling via ROCK2 drives the development of psoriasiform skin inflammation in Klk6+ mice and sought to identify whether KCs and/or T cells were pathogenically responsible. Klk6+ mice have increases in cutaneous ROCK2 activity compared with littermate controls that significantly decreases in the absence of Par1. However, following 4 weeks of systemic interference with ROCK2 signalling in Klk6+ mice, no improvement in skin inflammation was observed, despite ROCK2 activity levels decreasing to control mouse levels, indicating that the skin phenotype occurred in a ROCK2-independent manner. Next, we sought to identify whether Par1 on KCs or T cells was critical for the development of Klk6+ skin inflammation. Klk6+ mice were mated with KC (K14cre) or T-cell (Lckcre)-specific Par1 knockout mice (Parfl/ex). Both Klk6+-Par1ΔKC and Klk6+Par1ΔTcell mice developed significantly less severe skin inflammation than Klk6+ mice, demonstrated by overall improvement in appearance, significantly decreased acanthosis, and decreases in cutaneous T cells. Klk6-Par1 signalling in primary mouse T cells led to increases in Il17a and Ifng that retained their capacity to interact and elicit inflammatory signals from the KC, which was disrupted in T cells deficient in Par1. Together, these findings suggest that Klk6-Par1 signalling between T cells and keratinocytes is critical for skin inflammation and this occurs in a ROCK2-independent manner. These data provide new pathogenic insight into the cellular mechanisms underlying Klk6-Par1-mediated skin inflammation.
P49 Effectiveness of tildrakizumab for the treatment of plaque psoriasis in Austria with regard to itching
Journal: British Journal of Dermatology (2024)

Abstract Plaque psoriasis, an autoimmune disease predominantly affecting the skin, is accompanied by itching in 60–90% of the patients, which may seriously affect health-related quality of life (HRQoL). Female gender and high psoriasis area and severity index (PASI) scores are associated with more severe itch. Reduction of itch is one of the most desired treatment outcomes for patients. Tildrakizumab is an interleukin-23p19 inhibitor indicated for the treatment of moderate-to-severe plaque psoriasis with demonstrated long-term efficacy and safety.1 The primary objective of this study is to assess the improvement of itching in patients with plaque psoriasis under tildrakizumab therapy in routine care. The study is a monocentric, national, open, prospective, non-interventional, uncontrolled, single group, post-authorization, observational study carried out at a single study site in Austria for 28 weeks. Itch was assessed by the Numeric Rating Scale (NRS) 0–10 at each visit. Patients with medium-to-severe pruritus were eligible for inclusion in the study. The HRQoL instrument was Dermatology Life Quality Index-Relevant (DLQI-R). Effectiveness was assessed by PASI score. A total of 24 patients were included (58.0% male, mean age of 48 years, 42.0% current smokers). Seven patients had a family history of psoriasis and nine patients reported one or more comorbidities like obesity, dyslipidaemia, hypertension, and diabetes mellitus. The mean itch NRS score decreased from 7.3 at baseline to 2.7 at Week 4 and to 0.4 at Week 28. At baseline, 23 of 24 patients reported an itch NRS ≥4. In only 4 weeks, two-thirds of the patients (66.7%) reached the minimal clinically important difference reduction of ≥4 points, 18 of 23 at Week 16 and all of them at Week 28. At Week 4, after only one injection of tildrakizumab, 30.4% reported an itch NRS 0/1, and at Week 28 all but two patients reported no or minimal itch. The mean DLQI-R score decreased from 12.6 at baseline to 3.2 at Week 28. Mean PASI decreased from 13.2 at baseline to 0.6 at Week 28 which resulted in 91.3% of patients achieving PASI ≤1 at the end of the study. No patients discontinued due to adverse events. In a real-world setting, tildrakizumab quickly and effectively improved itch in psoriasis patients as well as skin symptoms and HRQoL, without safety concerns, and this improvement was maintained through Week 28.
P110 Zasocitinib (TAK-279) exhibits high levels of TYK2 inhibition and no inhibition of JAK 1/3 when compared with licensed TYK2 and JAK inhibitors
Journal: British Journal of Dermatology (2024)

Abstract Zasocitinib (TAK-279) is an oral, allosteric, highly selective, tyrosine kinase 2 (TYK2) inhibitor in late-stage clinical development for the treatment of immune-mediated inflammatory diseases, including psoriasis. Zasocitinib was developed using AI-assisted compound design strategy to create a TYK2 inhibitor with next-generation selectivity and &amp;gt;1 million-fold greater affinity for TYK2 than for Janus kinase (JAK) 1/2/3. This study compared the potency and selectivity of zasocitinib for TYK2 vs. JAK1/3 with licensed TYK2/JAK inhibitors. The inhibitory constants (Kis) of zasocitinib and deucravacitinib for JAK1 and TYK2 Janus homology 2 (JH2) domains were determined using a homogeneous time-resolved fluorescence assay. Fresh whole-blood cultures from 12 to 13 healthy volunteers characterized concentration–response (percentage inhibition) curves for TYK2- (IL-12/18 IFN-γ) and JAK1/3- (IL-2 pSTAT5) dependent pathways for zasocitinib and licensed TYK2/JAK inhibitors. Statistical modelling determined the relationship between concentration and percentage inhibition, and half-maximal inhibitory concentration (IC50) values were estimated. Drug plasma concentrations at clinically relevant/approved doses were simulated using published population pharmacokinetic models. Time over plasma concentrations &amp;gt;IC50 and percentage daily inhibition were compared between drugs for each pathway. The Kis of zasocitinib and deucravacitinib for the JAK1 JH2 domain were &amp;gt;15 000 and 1 nM, respectively. The Kis of zasocitinib and deucravacitinib for the TYK2 JH2 domain were 0.0087 and 0.0115 nM, respectively. Simulated plasma concentrations were above TYK2 IC50 for 24 h for zasocitinib 30 mg once daily (QD) vs. 3 h for deucravacitinib 6 mg QD, and 0 h for baricitinib 4 mg QD, tofacitinib 10 mg twice daily and upadacitinib 30 mg QD. TYK2 percentage daily inhibition was 91% for zasocitinib 30 mg and 23% for deucravacitinib 6 mg. Baricitinib 4 mg, upadacitinib 30 mg and tofacitinib 10 mg showed minimal TYK2 inhibition (0–8%). Simulated plasma concentrations of zasocitinib 30 mg and deucravacitinib 6 mg did not reach JAK1/3 IC50; those of baricitinib 4 mg, upadacitinib 30 mg and tofacitinib 10 mg were above JAK1/3 IC50 for 24 h. JAK1/3 percentage daily inhibition was 0% for zasocitinib 30 mg and 3% for deucravacitinib 6 mg vs. 91–97% for baricitinib 4 mg, upadacitinib 30 mg and tofacitinib 10 mg. Selective TYK2 inhibition offers a distinct cytokine receptor inhibition profile. Zasocitinib showed greater and longer selective inhibition of TYK2-mediated signalling vs. deucravacitinib at its clinical dosage, without affecting JAK1/3-mediated signalling.
P22 Psoriasis: impact on mental health
Journal: British Journal of Dermatology (2024)

Abstract Psoriasis is a chronic inflammatory condition with a major genetic component. While it predominantly affects the skin, psoriasis also has significant psychological effects. This literature review examines the impact of psoriasis on quality of life, with a particular focus on depression and anxiety. Additionally, it evaluates current mental health interventions and proposes strategies for enhancing these services. The aim of the study is to synthesize recent research findings on the impact of mental health due to psoriasis and discuss strategies to optimize the efficacy of psychological interventions. A systematic search was conducted across OVIDMedline and Embase using the search terms ‘psoriasis mental health’, ‘psoriasis depression’, ‘psoriasis anxiety’ and ‘psoriasis quality of life’. Inclusion criteria focused on articles published between 2019 and 2024 that focused on psoriasis and mental health. The review incorporated findings from 16 relevant articles of the identified 47 studies that met the inclusion criteria. Many studies included in the literature review used the Psoriasis Quality of Life Questionnaire to evaluate psychosocial negativities, difficulty in daily life and treatment difficulties. Prevalence of depression amongst individuals with psoriasis varied across the studies. Visibility of skin lesions, severity of the condition and gradual social isolation were the main contributory factors that led to psychological distress across these studies. Interventions such as Cognitive Behavioural Therapy, Support Groups and Relaxation Therapy1 can help combat body image issues and social stigma. However, there is limited literature, little implementation and sparse access to these interventions. Psoriasis is traditionally associated with psychiatric comorbidities such as stress, depression and anxiety.2 This review highlights the importance of addressing psychological well-being through the effective integration of mental health interventions into routine clinical practice. Future research should aim to innovate comprehensive and holistic patient care models that emphasise mental health and quality of life for those living with psoriasis.
P77 Bimekizumab in psoriatic disease: Exploring the fast onset, high level and durable clinical and molecular responses: design and rationale behind the exploratory, multicentre, open-label Phase 3b BE UNIQUE study
Journal: British Journal of Dermatology (2024)

Abstract Bimekizumab (BKZ) has shown rapid normalization of the psoriatic skin transcriptome and tissue-resident memory T-cell (Trm) signatures by Week (Wk)8, which may promote clinical response durability. Questions remain on the very early/longer-term effects of BKZ on key inflammatory pathways/mechanisms behind observed rapid, high, durable clinical responses in patients with psoriasis and psoriatic arthritis (PsA). We describe a study designed to investigate molecular/cellular changes associated with BKZ responses; we hypothesize that fast, durable, complete normalization of inflammatory biomarkers correlates with rapid, high, long-term clinical responses. BE UNIQUE is an ongoing multicentre Phase 3b study enrolling adults with moderate-to-severe psoriasis [psoriasis area and severity index (PASI) ≥12, body surface area (BSA) ≥10%, IGA ≥3]: 40 without concomitant PsA (Cohort A), 40 with concomitant active PsA (Cohort B). Active PsA is defined as disease meeting Classification Criteria for Psoriatic Arthritis, ≥1 tender joint count and ≥1 swollen joint count (SJC). In Part 1, patients will receive BKZ 320 mg every 4 weeks (Q4W) to Wk16, then Q8W to Wk48. In Part 2 (Wks48–96), patients with PASI = 0 [and low PsA activity for Cohort B (SJC≤1 and no increase in concomitant medications for PsA symptom treatment vs. baseline)] will be randomized 1:1 to BKZ Q8W or Q12W; patients with PASI &amp;gt;0 and/or without low PsA activity will continue on BKZ Q8W. Lesional skin biopsies will be taken at baseline/Wk1/48/96 and non-lesional skin biopsies at baseline/Wk48, with optional synovial tissue biopsy at baseline/Wk48 for Cohort B. Randomized patients with a PASI &amp;gt;3 during Part 2 will enter an escape period and receive BKZ Q8W to study end; a lesional skin biopsy will be taken on escape period entry, rather than Wk96. Biopsies will undergo transcriptomics. Blood samples will be collected. Baseline skin biopsies/blood samples will be taken from a matching Control Cohort (10 healthy individuals). Primary objective: assess gene expression score changes using reverse transcription-polymerase chain reaction of skin biopsies, using preselected genes based on BKZ mechanism of action/psoriatic disease pathways, including CCL20/CXCL1/CXCL8/IL12B/IL17A/IL17C/IL17F/IL23A/IL36A/IL36G/KRT16/S100A7, alongside markers of tissue-specific T-cell populations, for example, Trms. Secondary objective: evaluate BKZ safety/tolerability. Exploratory objectives include investigating BKZ effect on skin and blood bulk/single cell/spatial transcriptomics, BKZ systemic effects on gene/protein expression and BKZ clinical response. BE UNIQUE will enable the exploration of mechanisms underlying rapid, high, durable clinical responses observed with BKZ treatment and whether clinical response durability is associated with molecular/cellular changes in skin, blood and joints in psoriatic disease.