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Introduction: Secukinumab has demonstrated sustained long-term efficacy with a favourable safety profile in various manifestations of psoriatic disease. We investigated effectiveness and safety of secukinumab, other biologics and conventional systemic therapies in patients with chronic plaque psoriasis in a real-world setting. Methods: REALIA was a non-interventional, multicentre, prospective, parallel group study. Eligible patients were ≥ 18 years old with chronic plaque psoriasis commencing a new treatment with a biologic agent or conventional systemic therapies. Results: At baseline, 541 patients were divided into three cohorts based on treatment initiated: conventional systemics (173), secukinumab (184) and other biologics (184). A significantly higher proportion of patients achieved almost clear to clear skin based on physician's judgement in secukinumab versus conventional systemics at month 3 (64.7% versus 22.8%, P < 0.001) and month 6 (61.8% versus 20.8%, P < 0.001). At month 12, clear to almost clear skin was achieved by 52.1% of the patients in secukinumab versus 35.8% in conventional systemics (P = 0.066). The proportion of patients achieving Psoriasis Area Severity Index (PASI) 90 on conventional systemics, secukinumab and other biologics was 18.8%, 59.7% and 40.0% at month 3 and 35.3%, 60.8% and 50.0% at month 12, respectively. Secukinumab patients showed significantly higher change in PASI total score from baseline versus conventional systemics at month 3 {least squares [LS] mean [standard error (SE)]: −14.49 [0.648] versus −8.48 [1.149], P < 0.001} and numerically higher [LS mean (SE): −13.60 (0.475) versus −10.84 (1.733), P = 0.122] at month 12. The proportion of patients with Dermatology Life Quality Index 0/1 score on conventional systemics, secukinumab and other biologics was 22.6%, 65.0% and 41.6% at month 3 and 32.0%, 63.5% and 41.3% at month 12, respectively. Safety profile was comparable across cohorts. Conclusions: Secukinumab is effective and well tolerated in patients with chronic plaque psoriasis in a real-world setting in an Asia-Pacific and Middle East population, and these results are in agreement with clinical outcomes of secukinumab reported in randomised clinical trials. Trial registration number: 170803-001645. [ABSTRACT FROM AUTHOR]

Pruritus and skin discomfort/pain negatively impact health-related quality of life (HRQoL). The effects of apremilast, an oral phosphodiesterase 4 inhibitor, on pruritus, skin discomfort/pain, and patient global assessment of psoriasis disease activity (PgAPDA) were assessed in patients with moderate/severe chronic plaque psoriasis in the phase 3 ESTEEM trials. Significant improvements in pruritus and skin discomfort/pain observed at Week 2 with apremilast versus placebo (both studies, p < 0.0001) were sustained through Week 32. Among apremilast-treated patients, improvements in pruritus visual analog scale (VAS) scores correlated with Dermatology Life Quality Index scores (rs = 0.55 [Week 16]; rs≥ 0.51 [Week 32]; both studies, p < 0.001). PgAPDA correlated with improvements in pruritus (rs≥ 0.56 [Week 16]; rs≥ 0.53 [Week 32]; both studies, p < 0.001) and skin discomfort/pain (rs ≥ 0.54 [Week 16]; rs≥ 0.53 [Week 32]; both studies, p < 0.001) VAS scores. Apremilast provided rapid and sustained improvement in pruritus and skin discomfort/pain, symptoms not typically captured in psoriasis assessments (e.g., PASI) that contribute significantly to patients' disease severity and HRQoL perceptions. [ABSTRACT FROM AUTHOR]

Multiple Sclerosis (MS) is an autoimmune disease affecting the central nervous system, characterised by neuroinflammation and neurodegeneration. Fatigue and depression are common, debilitating, and intertwined symptoms in people with relapsing-remitting MS (pwRRMS). An increased understanding of brain changes and mechanisms underlying fatigue and depression in RRMS could lead to more effective interventions and enhancement of quality of life. To elucidate the relationship between depression and fatigue and brain connectivity in pwRRMS we conducted a systematic review. Searched databases were PubMed, Web-of-Science and Scopus. Inclusion criteria were: studied participants with RRMS (n ≥ 20; ≥ 18 years old) and differentiated between MS subtypes; published between 2001-01-01 and 2023-01-18; used fatigue and depression assessments validated for MS; included brain structural, functional magnetic resonance imaging (fMRI) or diffusion MRI (dMRI). Sixty studies met the criteria: 18 dMRI (15 fatigue, 5 depression) and 22 fMRI (20 fatigue, 5 depression) studies. The literature was heterogeneous; half of studies reported no correlation between brain connectivity measures and fatigue or depression. Positive findings showed that abnormal cortico-limbic structural and functional connectivity was associated with depression. Fatigue was linked to connectivity measures in cortico-thalamic-basal-ganglial networks. Additionally, both depression and fatigue were related to altered cingulum structural connectivity, and functional connectivity involving thalamus, cerebellum, frontal lobe, ventral tegmental area, striatum, default mode and attention networks, and supramarginal, precentral, and postcentral gyri. Qualitative analysis suggests structural and functional connectivity changes, possibly due to axonal and/or myelin loss, in the cortico-thalamic-basal-ganglial and cortico-limbic network may underlie fatigue and depression in pwRRMS, respectively, but the overall results were inconclusive, possibly explained by heterogeneity and limited number of studies. This highlights the need for further studies including advanced MRI to detect more subtle brain changes in association with depression and fatigue. Future studies using optimised imaging protocols and validated depression and fatigue measures are required to clarify the substrates underlying these symptoms in pwRRMS. [ABSTRACT FROM AUTHOR]

Introduction: Ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin-17A, is approved for treatment of moderate-to-severe plaque psoriasis. Our objective was to evaluate the long-term efficacy and safety of ixekizumab in moderate-to-severe plaque psoriasis through 5 years. Methods: Data were integrated from the UNCOVER-1 and UNCOVER-2, randomized, double-blinded, phase-3 trials. Patients who continuously received the labeled ixekizumab dose, were static Physician's Global Assessment (sPGA) (0,1) responders at Week 12 and completed 60 weeks of treatment could enter the long-term extension (LTE) period. Patients could escalate to every-2-week dosing per investigator opinion. Efficacy and health outcomes included proportion of patients achieving Psoriasis Area and Severity Index (PASI) 75/90/100, sPGA (0,1) and (0), absolute PASI ≤ 5/ ≤ 3/ ≤ 2/ ≤ 1 and Dermatology Life Quality Index (DLQI) (0,1). Results exclude patients who escalated to every-2-week dosing. A modified non-responder imputation method was used to account for missing data. Supplemental analyses include patients who escalated to every-2-week dosing and observed and multiple imputation results. Exposure-adjusted safety outcomes are also reported. Results: Of 206 patients who entered the LTE periods, 172 completed treatment. At Week 60, PASI 75/90/100 responses were 94.7%, 85.0% and 62.1%, respectively, and at year 5 were 90.3%, 71.3% and 46.3%, respectively. Similarly, meaningful responses were achieved for the other efficacy and health measures. Among patients with PASI 100 through 5 years, 92% achieved DLQI (0,1), indicating no impact of skin disease on quality of life. During the LTE period, exposure-adjusted incidence rates were 31.4 per 100 patient-years for treatment-emergent adverse events and 6.8 per 100 patient-years for serious adverse events. No deaths were reported. No new or unexpected safety findings were noted. Conclusions: The results demonstrate 80 mg ixekizumab maintains long-term efficacy and a safety profile consistent with previous data in patients with moderate-to-severe plaque psoriasis through 5 years of treatment. Trial Registration: ClinicalTrials.gov identifier, UNCOVER-1: NCT01474512, UNCOVER-2: NCT01597245. [ABSTRACT FROM AUTHOR]

OBJECTIVE To evaluate safety of stylet-in and stylet-out techniques for collection of CSF from the cisterna magna and to assess whether there were differences between techniques with regard to contamination of samples, sample quality, and efficiency of collection. ANIMALS 10 adult purpose-bred research Beagles. PROCEDURES A prospective crossover study was conducted. Preanesthetic physical and neurologic examinations and hematologic analyses were performed. Dogs were anesthetized, and collection of CSF samples from the cisterna magna by use of a stylet-in or stylet-out technique was performed. Two weeks later, samples were collected with the other sample collection technique. Samples of CSF were processed within I hour after collection. RESULTS Cellular debris was detected in higher numbers in stylet-in samples, although this did not affect sample quality. The stylet-out technique was performed more rapidly. No adverse effects were detected for either technique. CONCLUSIONS AND CLINICAL RELEVANCE Both techniques could be safely performed in healthy anesthetized dogs. The stylet-out technique was performed more rapidly and yielded a sample with less cellular debris. Both techniques can be used in clinical practice to yield CSF samples with good diagnostic quality. [ABSTRACT FROM AUTHOR]

A major obstacle toward creating human‐scale artificial tissue models is supplying encapsulated cells with oxygen and other nutrients throughout the construct. In particular, creating channels in hydrogels that match the resolution and density of the smallest blood capillaries (≤10 µm) remains highly challenging. Here, a novel method is demonstrated where polycaprolactone fibers printed using melt‐electrowriting are encapsulated in cell‐laden hydrogels and then physically removed to produce hollow, perfusable channels. This technique produces a range of channel diameters (10–41 µm) with circular cross‐sections and in hydrogels representing various crosslinking mechanisms. The channels can be formed as interconnected grids, hierarchically branched patterns, or stacked in layers with ≈200 µm channel spacing, thus matching average capillary density in the human body. Alternatively, selective removal of fibers from a melt electrowriting grid can generate perfusable channels within a reinforcing fiber network. This method can be performed in the presence of cells, with human fibroblasts exhibiting encapsulated in gelatin methacryloyl showing no detectable cytotoxic effects. This technique is a promising approach for creating perfusable channels with very small diameters within cell‐laden hydrogel matrices, with potential applications including in vitro tissue models and hydrogel microfluidics. [ABSTRACT FROM AUTHOR]

Atopic dermatitis is a chronic skin condition for which a range of systemic treatments have recently been approved. A treat-to-target strategy has been developed previously alongside an algorithm to guide the management of patients with atopic dermatitis. Here, we review the strategy and algorithm in the context of the evolving therapeutic landscape, and identify areas for further refinement and development. [ABSTRACT FROM AUTHOR]

Introduction: Deucravacitinib is an oral, selective tyrosine kinase 2 inhibitor that demonstrated therapeutic benefit in a Phase 2 clinical trial of adults with moderate to severe plaque psoriasis. This analysis was designed to evaluate the effect of deucravacitinib on additional clinical and quality-of-life (QoL) outcomes and assess the relationship between these outcomes in adults with psoriasis. Methods: Post-hoc analysis of a 12-week Phase 2 trial was conducted for the three most efficacious dosage groups (3 mg twice daily, 6 mg twice daily, 12 mg once daily) and placebo. Investigator assessments for efficacy included Psoriasis Area and Severity Index (PASI), body surface area (BSA) involvement, and static Physician's Global Assessment; QoL was assessed using the Dermatology Life Quality Index (DLQI). Treatment responses and their associations were evaluated over time. Results: Deucravacitinib elicited improvement versus placebo as early as Week 4 for most efficacy measures (including changes in absolute PASI and BSA), with efficacy trends observed from Week 2 to Week 12. Improvements in QoL, assessed by achievement of a DLQI overall score of 0/1 (no effect at all on patient's life), followed a pattern similar to deucravacitinib-related clinical outcomes over 12 weeks. Overall, patients with greater improvements in psoriasis-related clinical signs and symptoms also reported greater improvement in QoL. However, complete skin clearance was not required for achieving DLQI 0/1. Conclusion: Deucravacitinib treatment produced early response and similar trends in improvements across multiple efficacy assessments and QoL in moderate to severe plaque psoriasis. Deucravacitinib has the potential to become a promising new oral therapy for this condition. Trial Registration: ClinicalTrials.gov identifier; NCT02931838. Plain Language Summary: Psoriasis is a skin disease that affects up to 2% of the population. In psoriasis, red, scaly lesions develop on the skin driven by an aberrant immune response. Psoriasis impacts not only physical and mental health but also quality of life (QoL). Deucravacitinib is being investigated as a treatment for psoriasis. We performed a Phase 2 dose-ranging, placebo-controlled, 12-week study of deucravacitinib in adults with moderate to severe psoriasis. Patients in the USA, Australia, Canada, Germany, Japan, Latvia, Mexico, and Poland participated. The study showed that oral treatment with deucravacitinib was effective using a disease severity score (percentage of patients with ≥ 75% reduction from baseline in Psoriasis Area and Severity Index score) at Week 12—placebo 7% and deucravacitinib 67%–75% for the three highest dosages—and was generally well tolerated. We further analyzed the association between efficacy and a QoL measure, the Dermatology Life Quality Index (DLQI), in patients who received placebo or the most effective dosages of deucravacitinib (≥ 3 mg twice daily). Deucravacitinib was effective at the three dosage levels tested. Skin improvement occurred early during treatment and was mirrored by improvements in DLQI score during the 12 weeks of treatment. Although some patients did not have complete clearance of their psoriasis, a large percentage of those patients still achieved considerable improvement in QoL as measured by achieving a DLQI score of 0/1 (i.e., no effect at all on the patient's QoL). [ABSTRACT FROM AUTHOR]

Optimal management of atopic dermatitis requires a comprehensive assessment of response to treatment in order to inform therapeutic decisions. In a realworld setting, successful response to atopic dermatitis treatment is measured by sustained improvements in signs, symptoms, and quality of life. Post-hoc analyses of a 1-year, randomized, double-blinded, placebocontrolled trial (NCT02260986) of dupilumab with concomitant topical corticosteroids in 421 adults with moderate-to-severe atopic dermatitis (of whom 315/106 received placebo/dupilumab (of whom 315 received placebo and 106 received dupilumab) was performed to assess the proportion of responders to dupilumab through a multidimensional composite endpoint. At 6-months, 80.2% of dupilumab-treated vs 40.0% placebo patients (p < 0.0001) achieved improvement in signs (Eczema Area and Severity Index ≤ 7), symptoms (worst itch score ≤ 4), or quality of life (Dermatology Life Quality Index ≤5), representative of minimal/clear atopic dermatitis. All 3 endpoints, indicative of no/minimal atopic dermatitis, were achieved by 44.3% of dupilumab-treated vs 10.2% placebo patients (p < 0.0001) and sustained through 1 year. Dupilumab treatment provided sustained clinically meaningful improvement in signs, symptoms, and quality of life in adults with moderate-to-severe atopic dermatitis. [ABSTRACT FROM AUTHOR]

Introduction: Dupilumab is approved as first-line systemic treatment for adults/adolescents with moderate-to-severe atopic dermatitis (AD) in Europe and elsewhere owing to its favourable benefit–risk profile. However, systemic non-steroidal immunosuppressants (NSISS) are often used as first-line therapy in clinical practice. Impact of prior therapy with NSISS on dupilumab's treatment effect vs. control has not been described previously. This study assessed dupilumab's efficacy vs. control in patients with moderate-to-severe AD, comparing treatment effect in patients with/without prior systemic NSISS therapy, in four phase 3 trials. Methods: This post hoc analysis included 1553 patients randomized to placebo or dupilumab (300 mg q2w) as monotherapy for 16 weeks, or with concomitant topical corticosteroids (TCS) for 16/52 weeks, from four randomized, double-blind, placebo-controlled, phase 3 trials. Patients were stratified by prior use of systemic NSISS and dupilumab-treated patients were analysed against control groups (treated with placebo or placebo + TCS). Results: Dupilumab-treated patients, regardless of prior treatment with NSISS, achieved a significantly higher percentage reduction from baseline in Eczema Area and Severity Index (EASI), SCORing Atopic Dermatitis (SCORAD), Dermatology life Quality Index (DLQI), and Patient-Oriented Eczema Measure (POEM) vs. control; significantly more achieved EASI score ≤ 7, Peak Pruritus Numerical Rating Scale ≤ 4, POEM ≤ 7, and DLQI ≤ 5 by week 4. These rapid, significant improvements were seen with or without concomitant TCS and sustained through end-of-treatment. Conclusions: Dupilumab treatment (monotherapy or + TCS) provides rapid, significant, sustained improvements in signs, symptoms, and quality of life in patients with moderate-to-severe AD compared with control, regardless of prior systemic NSISS use. Clinical Trial Registration: LIBERTY AD SOLO 1: ClinicalTrials.gov identifier NCT02277743, EudraCT 2014-001198-15. LIBERTY AD SOLO 2: ClinicalTrials.gov identifier NCT02277769, EudraCT 2014-002619-40. LIBERTY AD CHRONOS: ClinicalTrials.gov identifier NCT02260986, EudraCT 2013-003254-24. LIBERTY AD CAFÉ: ClinicalTrials.gov identifier NCT02755649, EudraCT 2015-002653-35. Plain Language Summary: Atopic dermatitis (AD), also known as eczema, is characterized by red, oozy, and dry skin that can become cracked and infected. Dupilumab is a drug that blocks key molecules that cause allergic conditions, such as AD. It has been shown to be effective in treating moderate-to-severe AD. Other drugs commonly used to treat AD include certain anti-inflammatory drugs, known as non-steroidal immunosuppressants (NSISS), such as cyclosporin. It is not known if patients treated in the past with NSISS get the same results from AD treatment with dupilumab. This analysis used data from four large studies that included patients with moderate-to-severe AD. The objective was to see if prior NSISS use impacted how dupilumab worked to control AD. The researchers looked at a range of measurements—including ones that were assessed by a patient's doctor such as measurements of AD skin lesions. Itching and how patients felt about their overall life quality were also analysed (which included items such as sleep, pain, ability to work or do normal leisure activities, etc.). The researchers found that if a patient had taken an NSISS for AD before taking dupilumab, it had no impact on the efficacy of dupilumab. All of the measurements evaluated improved significantly more in patients treated with dupilumab than in patients taking a placebo (dummy) medication. The benefits of treatment occurred within a few weeks of starting dupilumab treatment and remained until the end of the longest study included in this analysis, 1 year. [ABSTRACT FROM AUTHOR]

Background: Meningitis is a very rare atypical presenting feature of anti-NMDA receptor encephalitis. In our case report, we describe an unusual clinical presentation of anti-NMDA receptor encephalitis with a biphasic pattern of meningitis followed by encephalitis and discuss potential mechanisms underlying this presentation. We aim to widen the differential diagnosis to be considered in a patient presenting with clinical meningitis and pyrexia.Case Presentation: This is a case of a 33-year old Caucasian woman who initially presented with a lymphocytic meningitis attributed to a viral infection. She subsequently developed fluctuating consciousness, agitation, visual hallucinations, dyskinetic movements, a generalized tonic-clonic seizure, and autonomic instability. Investigations revealed a diagnosis of anti-NMDA receptor encephalitis secondary to a previously unidentified ovarian teratoma. She made an excellent recovery with immunotherapy and removal of the teratoma.Conclusion: Clinicians should consider autoimmune encephalitides in individuals with meningitis, particularly where extensive investigations fail to identify a causative pathogen and there is rapid development of an encephalitic phenotype. [ABSTRACT FROM AUTHOR]

Graves' orbitopathy (GO) is uncommon, but responsible for considerable morbidity. A coordinated approach between healthcare professionals is required in order to meet the needs of patients. Early diagnosis can be achieved by a simple clinical assessment. Low-cost effective interventions can be initiated by generalists, which may improve outcomes. Moderate-to-severe GO should be referred to specialised centres. Recommendations for clinical diagnosis, initial management and referral pathways are highlighted. [ABSTRACT FROM AUTHOR]