Navigating the evolving landscape of atopic dermatitis: Challenges and future opportunities: The 4th Davos declaration.

The 4th Davos Declaration was developed during the Global Allergy Forum in Davos which aimed to elevate the care of patients with atopic dermatitis (AD) by uniting experts and stakeholders. The forum addressed the high prevalence of AD, with a strategic focus on advancing research, treatment, and management to meet the evolving challenges in the field. This multidisciplinary forum brought together top leaders from research, clinical practice, policy, and patient advocacy to discuss the critical aspects of AD, including neuroimmunology, environmental factors, comorbidities, and breakthroughs in prevention, diagnosis, and treatment. The discussions were geared towards fostering a collaborative approach to integrate these advancements into practical, patient-centric care. The forum underlined the mounting burden of AD, attributing it to significant environmental and lifestyle changes. It acknowledged the progress in understanding AD and in developing targeted therapies but recognized a gap in translating these innovations into clinical practice. Emphasis was placed on the need for enhanced awareness, education, and stakeholder engagement to address this gap effectively and to consider environmental and lifestyle factors in a comprehensive disease management strategy. The 4th Davos Declaration marks a significant milestone in the journey to improve care for people with AD. By promoting a holistic approach that combines research, education, and clinical application, the Forum sets a roadmap for stakeholders to collaborate to improve patient outcomes in AD, reflecting a commitment to adapt and respond to the dynamic challenges of AD in a changing world.

Real-world effectiveness and safety of tildrakizumab in long-term treatment of plaque psoriasis: Results from the non-interventional, prospective, multicentre study TILOT.

BACKGROUND: Plaque psoriasis is a chronic inflammatory disorder affecting the skin and impacting quality of life. Tildrakizumab (TIL) is an IL-23 inhibitor licensed for moderate-to-severe plaque psoriasis. Regulatory approval of medicinal products is based on safety and efficacy data from randomized controlled trials (RCTs) which impose stringent selection criteria. Long-term non-interventional studies (NIS) are needed to establish effectiveness and safety in daily practice bridging the gap between RCTs and the real-world setting. OBJECTIVES: This analysis of the NIS TILOT seeks to evaluate effectiveness and safety of TIL in patients with moderate-to-severe plaque psoriasis in a real-world setting. Secondary objectives include the assessment of the Dermatology Life Quality Index (DLQI), treatment satisfaction and course of scalp and nail disease using Physician Global Assessment (PGA). METHODS: Interim analysis at 52 weeks (W) of the ongoing non-interventional, prospective, long-term multicentre study TILOT. RESULTS: The effectiveness analysis included 412 patients. The mean [standard deviation, SD] Psoriasis Area and Severity Index (PASI) score was 16.0 [9.1] at baseline improving by 82.4% (95% confidence interval [CI], 78.9-86.0) to 2.1 [2.9] at W52. The proportion of patients achieving PASI scores of <3 and <5 increased over time peaking at 74.6% (95% CI, 69.3-79.4) and 88.4% (95% CI, 84.3-91.8) at W52. Scalp-PGA and nail-PGA improved by 79.8% (95% CI, 75.6-84.0) and 72.7% (95% CI, 63.9-81.6), respectively. DLQI of 0/1 was achieved by 48.2% (95% CI, 42.3-54.2). Nine out of 10 physicians and patients expressed a high level of treatment satisfaction. No new safety signals were observed. CONCLUSIONS: This prospective cohort study demonstrates a high degree of effectiveness and a reassuring safety profile of TIL in a real-world setting over 52 weeks. Patients with scalp and nail involvement or pruritus showed marked improvements.

Pifithrin-α provides neuroprotective effects at the level of mitochondria independently of p53 inhibition.

Impaired mitochondrial integrity and function are key features of intrinsic death pathways in neuronal cells. Therefore, key regulators of intrinsic death pathways acting upstream of mitochondria are potential targets for therapeutic approaches of neuroprotection. The tumor suppressor p53 is a well-established regulator of cellular responses towards different kinds of lethal stress, including oxidative stress. Recent reports suggested that p53 may affect mitochondrial integrity and function through both, transcriptional activation of mitochondria-targeted pro-death proteins and direct effects at the mitochondrial membrane. In the present study, we compared the effects of pharmacological inhibition of p53 by pifithrin-α with those of selective p53 gene silencing by RNA interference. Using MTT assay and real-time cell impedance measurements we confirmed the protective effect of both strategies against glutamate-induced oxidative stress in immortalized mouse hippocampal HT-22 neurons. Further, we observed full restoration of mitochondrial membrane potential and inhibition of glutamate-induced mitochondrial fragmentation by pifithrin-α which was, in contrast, not achieved by p53 gene silencing. Downregulation of p53 by siRNA decreased p53 transcriptional activity and reduced expression levels of p21 mRNA, while pifithrin-α did not affect these endpoints. These results suggest a neuroprotective effect of pifithrin-α which occurred at the level of mitochondria and independently of p53 inhibition.

Introducing a simplified titration scheme for dimethylfumarate (DMF) in patients with moderate-to-severe psoriasis: a case series.

Dimethylfumarate (DMF) is approved for the treatment of moderate to severe psoriasis. In clinical practice, DMF tolerability is improved by slowly up-titrating the dose. Time-to-onset of gastrointestinal complaints (a common adverse event [AE]) is ∼4 weeks, coinciding with the increase in dose to one 120-mg tablet. The average DMF dose during maintenance treatment is also often lower than the maximum indicated dose of 720 mg/day. Here, a simplified dose-escalation strategy is described, where twice-daily DMF was up-titrated to a maximum of 720 mg/day (if required) in week 7. Ten patients received DMF according to the new scheme (maximum dose: 720 mg/day [n = 5], 480 mg/day [n = 3; escalation halted early due to good efficacy], and ≤240 mg/day [n = 2] by week 12). Mean Psoriasis Area Severity Index (PASI) decreased from 7.2 to 0.9 between weeks 0 and 24. Absolute Psoriasis Area Severity Index (aPASI) was ≤3 for 7 and 6 patients at weeks 12 and 24, respectively. Affected BSA and DLQI demonstrated similar improvements. Treatment was terminated in 3 patients due to AEs (diarrhea and lymphopenia). In this case series, simplified DMF dosing was largely well-tolerated and provided similar efficacy to the current scheme. Higher doses were reached more quickly and the dosing regimen was simpler for patients (twice instead of three times daily).

Long-Term Treatment with Dimethyl Fumarate for Plaque Psoriasis in Routine Practice: Good Overall Effectiveness and Positive Effect on Impactful Areas.

INTRODUCTION: Dimethyl fumarate (DMF) is an oral compound to treat plaque psoriasis. Data on the treatment of patients with psoriasis affecting impactful areas are scarce. In this interim analysis of the prospective, noninterventional SKILL study, we summarized results of DMF treatment regarding effectiveness (overall and in impactful areas) and safety. METHODS: Data from 676 patients suffering from moderate-to-severe plaque psoriasis were analyzed after 52 weeks of DMF treatment. Of these, 257 had data available after 52 weeks. The considered impactful areas were nails, palms, soles, and scalp. Data analysis included observed cases (OC) and last observation carried forward (LOCF). RESULTS: All effectiveness parameters improved after 52 weeks. The Psoriasis Area and Severity Index score was reduced by 79.5% (OC) and 65.7% (LOCF). Compared with baseline, improvements were shown for 70.2% of the patients in their nail psoriasis [nail-Physician Global Assessment (PGA)] and for 57.3% in palmoplantar disease (palmoplantar-PGA). The proportion of patients with scalp-PGA 0/1 (clear/almost clear) increased significantly to 79.8% (OC) and 69.3% (LOCF, both p < 0.001) (versus 37.5% and 36.6% at baseline, respectively). Significant reduction of pruritus (p < 0.001) was also observed. No unexpected adverse drug reactions were observed. CONCLUSION: Long-term treatment with DMF in routine practice showed good overall effectiveness and safety, and a positive effect on plaque-psoriasis-affected impactful areas.

Response to fumaric acid esters for plaque type psoriasis in real-world practice is largely independent of patient characteristics at baseline - a multivariable regression analysis from the German Psoriasis Registry PsoBest.

OBJECTIVES: Fumaric acid esters (FAEs) are a well-established treatment option for long-term therapy of moderate to severe plaque psoriasis. This study examines effectiveness of FAEs for the treatment of plaque psoriasis in real-world practice at 12 months and if patient characteristics affect the odds of clinical response. METHODS: A descriptive, multivariable logistic regression analysis was conducted in a cohort drawn from the German registry PsoBest. Baseline patient characteristics were assessed as potential treatment effect modifiers. RESULTS: 444 patients (mean age 47.0 years, 39.0% female) were eligible for response analysis using nonresponder imputation at month 12. Of these, 39.6% achieved clinical response, i.e. Psoriasis Area and Severity Index (PASI) ≤ 3 or skin clearance. In logistic regression analysis (R2 = 0.114), only baseline PASI was a significant factor: patients with PASI < 10 had a 4 times higher odds (p ≤ .001, OR 4.088), patients with PASI of 10-20 a twofold higher odds of response (p ≤ .044, OR 1.961) compared to those with PASI > 20. Neither sex, age, body weight, disease duration, comorbidity nor pretreatment had an impact on the odds of response (p > .05). CONCLUSIONS: FAEs showed a favorable response at 12 months, largely independent of patient characteristics.

Efficacy of dimethyl fumarate treatment for moderate-to-severe plaque psoriasis: presentation extracts from the 29th EADV virtual congress, 29-31 October 2020.

Background: The 29th EADV Virtual Congress took place between the 29th-31st of October 2020. On October 29th, there was a Session on systemic treatment in which Professors Ulrich Mrowietz and Mar Llamas-Velasco presented the latest research on the efficacy of dimethyl fumarate (DMF) treatment for moderate-to-severe plaque psoriasis (BRIDGE and DIMESKIN 1 studies, respectively). The accepted DMF abstract from Professor Matthias Augustin, on the SKILL study, is also presented here. Results: Data from either prospective interventional (BRIDGE) or non-interventional (DIMESKIN 1, SKILL) studies among patients with moderate-to-severe psoriasis showed that DMF provides a positive efficacy profile in all four body regions included in the Psoriasis Area and Severity Index assessment (head and neck, trunk, upper and lower extremities) and a particularly interesting profile (strong efficacy) in the head and neck region. These findings may be of special interest to patients with scalp psoriasis who have been using topical therapies for a long time. Patient-reported outcomes (quality of life, pruritus) also improved during the 24 weeks of DMF treatment. The safety profile of DMF was similar to the previously described with fumaric acid esters. Conclusions: In summary, these results confirm the favorable efficacy and safety profile of DMF in long-term treatment.

Cylindromatosis mediates neuronal cell death in vitro and in vivo.

The tumor-suppressor cylindromatosis (CYLD) is a deubiquitinating enzyme and key regulator of cell proliferation and inflammation. A genome-wide siRNA screen linked CYLD to receptor interacting protein-1 (RIP1) kinase-mediated necroptosis; however, the exact mechanisms of CYLD-mediated cell death remain unknown. Therefore, we investigated the precise role of CYLD in models of neuronal cell death in vitro and evaluated whether CYLD deletion affects brain injury in vivo. In vitro, downregulation of CYLD increased RIP1 ubiquitination, prevented RIP1/RIP3 complex formation, and protected neuronal cells from oxidative death. Similar protective effects were achieved by siRNA silencing of RIP1 or RIP3 or by pharmacological inhibition of RIP1 with necrostatin-1. In vivo, CYLD knockout mice were protected from trauma-induced brain damage compared to wild-type littermate controls. These findings unravel the mechanisms of CYLD-mediated cell death signaling in damaged neurons in vitro and suggest a cell death-mediating role of CYLD in vivo.