A Review of Biologic Therapies Targeting IL-23 and IL-17 for Use in Moderate-to-Severe Plaque Psoriasis

International audienceThis paper presents numerical crack propagations in case of explicit dynamics, and applied to eXtended Finite Element Method. The interest of this method is non remeshing. Hence the crack propagates through the constant mesh. Only some elements cut by the crack can have critical time step close to zero. To avoid this case, the lumping technique of mass matrix will allow to obtain the same critical time step than the case without crack: a crack and its propagation do not modify the critical time step of the whole structure. To conclude, we have $\Delta t_\text{c}^\text{X-FEM} = \Delta t_\text{c}^\text{FEM}$ for some elements.Ce papier traite de la simulation numérique de propagation dynamique de fissure dans le cas particulier de calcul explicite, et appliquée à la méthode des éléments finis étendus. L'intérêt de cette méthode est le non-remaillage. Effectivement, la fissure se propage dans le maillage invariant. Seulement certains éléments, coupés par la fissure, peuvent avoir des pas de temps critiques de calcul presque nuls. Pour s'affranchir de ces cas pénalisant le calcul, la méthode de diagonalisation de matrice de masse va permettre d'obtenir le même pas de temps critique que le cas sans fissure : l'introduction d'une fissure et sa propagation ne modifie pas le pas de temps critique de la structure. Au final, on a dans certains cas $\Delta t_\text{c}^\text{X-FEM} = \Delta t_\text{c}^\text{FEM}$

Emerging Therapies for the Treatment of Psoriasis

Psoriasis is an immune-mediated disease that affects 1%–2% of the European and North American population. While topical agents such as corticosteroids and vitamin D derivatives are prescribed for mild disease, they are generally unable to adequately control patients with more severe disease. Over the past decade, research into the immunopathogenesis of psoriasis, including investigations into the role of tumor necrosis factor-alpha and more recently interleukins (IL) 12/23, has led to the advent of targeted biologic therapies based on the central role of a new subset of T cells, Th17. Because of their increased specificity, biologic agents have revolutionized short- to medium-term treatment outcomes and safety profiles for moderate to severe disease over previously gold standard systemic agents. The immunopathogenesis of the disease is still a focus for researchers and novel targets for future agents are being discovered and investigated in clinical trials. In particular, specifically targeting the IL-23/Th17 pathway has given rise to IL-23p19 and IL-17 antagonists, both of which have shown significant promise in clinical trials. IL-22 is involved in keratinocyte proliferation and is being studied as a treatment target for psoriasis. New small molecule oral agents, including Janus kinase and phosphodiesterase inhibitors are currently in phase 2 and 3 clinical trials

A subset of methylated CpG sites differentiate psoriatic from normal skin.

Psoriasis is a chronic inflammatory immune-mediated disorder affecting the skin and other organs including joints. Over 1,300 transcripts are altered in psoriatic involved skin compared with normal skin. However, to our knowledge, global epigenetic profiling of psoriatic skin is previously unreported. Here, we describe a genome-wide study of altered CpG methylation in psoriatic skin. We determined the methylation levels at 27,578 CpG sites in skin samples from individuals with psoriasis (12 involved, 8 uninvolved) and 10 unaffected individuals. CpG methylation of involved skin differed from normal skin at 1,108 sites. Twelve mapped to the epidermal differentiation complex, upstream or within genes that are highly upregulated in psoriasis. Hierarchical clustering of 50 of the top differentially methylated (DM) sites separated psoriatic from normal skin samples with uninvolved skin exhibiting intermediate methylation. CpG sites where methylation was correlated with gene expression are reported. Sites with inverse correlations between methylation and nearby gene expression include those of KYNU, OAS2, S100A12, and SERPINB3, whose strong transcriptional upregulation is an important discriminator of psoriasis. Pyrosequencing of bisulfite-treated DNA from skin biopsies at three DM loci confirmed earlier findings and revealed reversion of methylation levels toward the non-psoriatic state after 1 month of anti-TNF-α therapy

Repeat courses of intravenous alefacept in patients with chronic plaque psoriasis provide consistent safety and efficacy

Background Psoriasis is a chronic, relapsing skin disease that may require multiple treatment courses. Alefacept targets the memory T cells implicated in psoriasis pathogenesis. This open-label study evaluated the safety and tolerability, efficacy, and pharmacodynamics of repeat courses of alefacept in men and women with chronic plaque psoriasis. This article reports the interim results of this ongoing study. Methods Patients ( n  = 174) who participated in previous phase II studies of alefacept were included in this retreatment study. Intravenous alefacept (7.5 mg) was administered once weekly for 12 weeks followed by 12 weeks of observation. Initial and subsequent retreatment courses were only given when, in the opinion of the investigators, disease had returned and necessitated treatment; CD4 + T-cell counts had to be at or above the lower limit of normal. Results Adverse events were similar regardless of the retreatment course. No opportunistic infections, rebound of disease, or flares were reported. Low titers of anti-alefacept antibodies occurred in a few patients without related safety issues. Sixty-six per cent of patients achieved a ≥ 50% reduction in the Psoriasis Area and Severity Index (PASI) at any time after the first dose of retreatment course 1. Patients who received two retreatment courses ( n  = 50) had consistent or improved responses after the second course; 64% and 68% of these patients achieved a ≥ 50% PASI improvement at any time after the first dose of retreatment courses 1 and 2, respectively. Alefacept selectively reduced memory T cells without cumulative effects. Conclusions Repeat courses of alefacept were well tolerated, and subsequent retreatment courses were at least as effective as the initial course of therapy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65825/1/j.1365-4362.2003.01793.x.pd

Adalimumab improves health-related quality of life in patients with moderate to severe plaque psoriasis compared with the United States general population norms: Results from a randomized, controlled Phase III study

<p>Abstract</p> <p>Objective</p> <p>To evaluate the impact of adalimumab on health-related quality of life (HRQOL) for patients with moderate to severe plaque psoriasis.</p> <p>Background</p> <p>Psoriasis is a chronic, inflammatory, immune-mediated disease that has a significant impact on patients' HRQOL. Adalimumab is a fully human monoclonal antibody that blocks tumor necrosis factor, a pro-inflammatory cytokine, and is effective and well-tolerated for patients with moderate to severe psoriasis.</p> <p>Methods</p> <p>Data were obtained for a secondary analysis of patients in a randomized, controlled Phase III trial evaluating the effect of adalimumab in patients with psoriasis (N = 1,205). Patients with moderate to severe psoriasis were randomized in a 2:1 ratio to adalimumab 80 mg (two 40 mg injections administered subcutaneously at baseline followed by one 40 mg injection every other week from Week 1 to Week 15) or placebo. Short Form-36 (SF-36) Health Survey scores of psoriasis patients were used to assess HRQOL and were compared with United States (US) population norms at baseline and Week 16.</p> <p>Results</p> <p>Baseline Physical Component Summary (PCS) scores for the placebo and adalimumab groups were similar to the general US population. Baseline mean Mental Component Summary (MCS) scores were significantly lower for the adalimumab and placebo groups compared with the general population (47.4, 47.7, and 50.8 points, respectively; p < 0.0001). PCS scores at Week 16 for patients receiving adalimumab had improved and were significantly greater than scores for the general US population (52.7 vs 48.9; p < 0.001). Compared with the general US population, MCS scores at Week 16 were similar for patients receiving adalimumab (51.2 vs 50.8; p = 1.000) and lower for patients receiving placebo (50.8 vs 48.7; p < 0.0001).</p> <p>Conclusion</p> <p>Psoriasis has a broad impact on patient functioning and well-being. Improvement in skin lesions and joint symptoms associated with adalimumab treatment was accompanied by improvements in HRQOL to levels that were similar to or greater than those of the general US population.</p> <p>Trial registration</p> <p>Clinicaltrials.gov NCT00237887</p

IL-4Rα Blockade by Dupilumab Decreases Staphylococcus aureus Colonization and Increases Microbial Diversity in Atopic Dermatitis.

Dupilumab is a fully human antibody to interleukin-4 receptor α that improves the signs and symptoms of moderate to severe atopic dermatitis (AD). To determine the effects of dupilumab on Staphylococcus aureus colonization and microbial diversity on the skin, bacterial DNA was analyzed from swabs collected from lesional and nonlesional skin in a double-blind, placebo-controlled study of 54 patients with moderate to severe AD randomized (1:1) and treated with either dupilumab (200 mg weekly) or placebo for 16 weeks. Microbial diversity and relative abundance of Staphylococcus were assessed by DNA sequencing of 16S ribosomal RNA, and absolute S.&nbsp;aureus abundance was measured by quantitative PCR. Before treatment, lesional skin had lower microbial diversity and higher overall abundance of S.&nbsp;aureus than nonlesional skin. During dupilumab treatment, microbial diversity increased and the abundance of S.&nbsp;aureus decreased. Pronounced changes were seen in nonlesional and lesional skin. Decreased S.&nbsp;aureus abundance during dupilumab treatment correlated with clinical improvement of AD and biomarkers of type 2 immunity. We conclude that clinical improvement of AD that is mediated by interleukin-4 receptor α inhibition and the subsequent suppression of type 2 inflammation is correlated with increased microbial diversity and reduced abundance of S.&nbsp;aureus

Five-year analysis from the ESPRIT 10-year postmarketing surveillance registry of adalimumab treatment for moderate to severe psoriasis

BackgroundESPRIT is an ongoing, 10-year, observational registry, evaluating long-term safety and effectiveness of adalimumab treatment in routine clinical practice for patients with moderate to severe, chronic plaque psoriasis.ObjectivesInitial 5-year results are reported.MethodsTwo populations were analyzed: the “all-treated” population received 1 or more adalimumab doses in registry, continuing adalimumab treatment from a current prescription or previous study participation, and included the “new-prescription” population initiating adalimumab 4 weeks or earlier preregistry entry.ResultsData were collected from September 26, 2008, through November 30, 2013, for all-treated (n = 6059), which included new-prescription (n = 2580, 42.6%); median registry exposure was 765 and 677 days, respectively. In all-treated, rate (events per 100 patient-years of total adalimumab exposure [E/100PY]) of serious treatment-emergent adverse events (inside or outside of the registry) was 4.3 E/100PY, serious infection 1.0 E/100PY, malignancies 0.9 E/100PY (nonmelanoma skin cancers 0.6 E/100PY; melanomas <0.1 E/100PY). Standardized mortality ratio was 0.30 (95% confidence interval 0.19-0.44). Physician Global Assessment clear or minimal (effectiveness parameter) was achieved by 57.0% at 12 months and 64.7% at 60 months of treatment.LimitationsObservational data are subject to outcome-reporting bias.ConclusionNo new safety signals were observed with adalimumab treatment during this initial 5-year registry review. Observed number of deaths was below expected. As-observed effectiveness remained stable through 60 months

Clinical Symptoms of Skin, Nails, and Joints Manifest Independently in Patients with Concomitant Psoriasis and Psoriatic Arthritis

This study correlated assessment tools for evaluating the severity of skin, nail, and joint symptoms in patients with psoriasis (Pso) and psoriatic arthritis (PsA). Adults with plaque Pso (with or without PsA) were enrolled from four U.S. institutions. Patients were evaluated using a novel 10-area Linear Psoriasis Area and Severity Index (XL-PASI), Psoriatic Arthritis Assessment (PsAA), Psoriatic Arthritis Screening and Evaluation Questionnaire (PASE), Nail Assessment (NA) and Joint Assessment (JA) tools, Psoriasis Weighted Extent and Severity Index (PWESI), and Lattice Physician Global Assessment (LS-PGA). Correlations between assessment tools and individual items in the assessment tools were performed. Data from 180 patients (55 with PsA) were analyzed. Highest correlations between tools (r = 0.77–0.88) were between the XL-PASI, PWESI and LS-PGA. Individual items in the XL-PASI correlated with items in the PWESI for extent skin symptoms, but not for all body areas. Overall, correlations were seen between hands and feet, between face and scalp, and between buttocks, chest, and back. Only low correlation was seen between items assessing joint symptoms with items assessing skin symptoms. These data support the notion that the complex phenotype of psoriatic disease requires instruments that assess the severity of skin, nails, and joints separately

Predictions of Heat Transfer and Flow Circulations in Differentially Heated Liquid Columns With Applications to Low-Pressure Evaporators

Numerical computations are presented for the temperature and velocity distributions of two differentially heated liquid columns with liquor depths of 0.1 m and 2.215 m, respectively. The temperatures in the liquid columns vary considerably with respect to position for pure conduction, free convection, and nucleate boiling cases using one-dimensional (1D) thermal resistance networks. In the thermal resistance networks the solutions are not sensitive to the type of condensing and boiling heat transfer coefficients used. However, these networks are limited and give no indication of velocity distributions occurring within the liquor. To alleviate this issue, two-dimensional (2D) axisymmetric and three-dimensional (3D) computational fluid dynamics (CFD) simulations of the test rigs have been performed. The axisymmetric conditions of the 2D simulations produce unphysical solutions; however, the full 3D simulations do not exhibit these behaviors. There is reasonable agreement for the predicted temperatures, heat fluxes, and heat transfer coefficients when comparing the boiling case of the 1D thermal resistance networks and the CFD simulations

IL-4R alpha blockade by dupilumab decreases Staphylococcus aureus colonization and increases microbial diversity in atopic dermatitis

Dupilumab is a fully human antibody to interleukin-4 receptor alpha that improves the signs and symptoms of moderate to severe atopic dermatitis (AD). To determine the effects of dupilumab on Staphylococcus aureus colonization and microbial diversity on the skin, bacterial DNA was analyzed from swabs collected from lesional and nonlesional skin in a double-blind, placebo-controlled study of 54 patients with moderate to severe AD randomized (1:1) and treated with either dupilumab (200 mg weekly) or placebo for 16 weeks. Microbial diversity and relative abundance of Staphylococcus were assessed by DNA sequencing of 16S ribosomal RNA, and absolute S. aureus abundance was measured by quantitative PCR. Before treatment, lesional skin had lower microbial diversity and higher overall abundance of S. aureus than nonlesional skin. During dupilumab treatment, microbial diversity increased and the abundance of S. aureus decreased. Pronounced changes were seen in nonlesional and lesional skin. Decreased S. aureus abundance during dupilumab treatment correlated with clinical improvement of AD and biomarkers of type 2 immunity. We conclude that clinical improvement of AD that is mediated by interleukin-4 receptor alpha inhibition and the subsequent suppression of type 2 inflammation is correlated with increased microbial diversity and reduced abundance of S. aureus