Search

Additional long-term treatments are needed for moderate-to-severe atopic dermatitis (AD). An ongoing, open-label, 5-year extension trial, ECZTEND (NCT03587805), assesses tralokinumab plus optional topical corticosteroids in participants from previous tralokinumab parent trials (PTs) with moderate-to-severe AD.To evaluate the safety and efficacy of up to 2 years tralokinumab treatment in a post hoc interim analysis.Safety analyses included adults from completed PTs enrolled in ECZTEND, regardless of tralokinumab exposure duration. Efficacy analyses included adult participants treated with tralokinumab in ECZTEND for ≥1 year and subgroup analyses of those on tralokinumab for 2 years (1 year from PT, 1 year in ECZTEND). Primary end point was the number of adverse events with additional efficacy end points.Participants on tralokinumab had an exposure-adjusted rate of 237.8 adverse events/100 patient-years' exposure (N = 1174) in the safety analysis set. Exposure-adjusted incidence rates of common adverse events were comparable to PTs, although at lower rates. With 2 years of tralokinumab, improvements in extent and severity of AD were sustained, with Eczema Area and Severity Index (EASI-75) in 82.5% of participants (N = 345).Possible selection bias; no placebo arm; some participants experienced treatment gaps between PTs and ECZTEND.Over 2 years, tralokinumab was well tolerated and maintained long-term control of AD signs and symptoms.

A stratified medicine approach for the treatment of psoriasis promises greater certainty of clinical decision making through prediction of response on the basis of clinical, pharmacological, and -omics data from an individual patient. As yet, there is no predictive model for treatment response in routine clinical use for psoriasis. The Psoriasis Stratification to Optimise Relevant Therapy (PSORT) Consortium is a United Kingdom Medical Research Council‒funded, academic‒industrial stratified medicine consortium established with the objective of discovering the predictors and stratifiers of response of psoriasis to biologic therapies. A showcase meeting was convened and attended by 80 stakeholders at the Royal College of Physicians, London, United Kingdom on 18 November 2019. The purpose was to disseminate the research findings from the PSORT consortium discovered thus far. This report summarizes the presentations made on the day and the significant advances made by PSORT toward a stratified medicine approach to the management of psoriasis.

There is an unmet need for a treatment for psoriasis that results in complete skin clearance with a reliably quick response. Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A. We aimed to compare the efficacy and safety of bimekizumab with placebo and ustekinumab in patients with moderate to severe plaque psoriasis over 52 weeks.BE VIVID was a multicentre, randomised, double-blind, active comparator and placebo controlled phase 3 trial done across 105 sites (clinics, hospitals, research units, and private practices) in 11 countries in Asia, Australia, Europe, and North America. Adults aged 18 years or older with moderate to severe plaque psoriasis (Psoriasis Area and Severity Index [PASI] score ≥12, ≥10% body surface area affected by psoriasis, and Investigator's Global Assessment [IGA] score ≥3 on a five point scale) were included. Randomisation was stratified by geographical region and previous exposure to biologics; patients, investigators, and sponsors were masked to treatment assignment. Patients were randomly assigned (4:2:1) using an interactive response technology to bimekizumab 320 mg every 4 weeks, ustekinumab 45 mg or 90 mg (baseline weight-dependent dosing) at weeks 0 and 4, then every 12 weeks, or placebo every 4 weeks. At week 16, patients receiving placebo switched to bimekizumab 320 mg every 4 weeks. All study treatments were administered as two subcutaneous injections. Coprimary endpoints were the proportion of patients with 90% improvement in the PASI (PASI90) and the proportion of patients with an IGA response of clear or almost clear (score 0 or 1) at week 16 (non-responder imputation). Efficacy analyses included the intention-to-treat population; safety analysis included patients who received at least one dose of study treatment. This trial was registered at ClinicalTrials.gov, NCT03370133 (completed).Between Dec 6, 2017, and Dec 13, 2019, 735 patients were screened and 567 were enrolled and randomly assigned (bimekizumab 320 mg every 4 weeks n=321, ustekinumab 45 mg or 90 mg every 12 weeks n=163, placebo n=83). At week 16, 273 (85%) of 321 patients in the bimekizumab group had PASI90 versus 81 (50%) of 163 in the ustekinumab group (risk difference 35 [95% CI 27-43]; p0·0001) and four (5%) of 83 in the placebo group (risk difference 80 [74-86]; p0·0001). At week 16, 270 (84%) patients in the bimekizumab group had an IGA response versus 87 (53%) in the ustekinumab group (risk difference 30 [95% CI 22-39]; p0·0001) and four (5%) in the placebo group (risk difference 79 [73-85]; p0·0001). Over 52 weeks, serious treatment-emergent adverse events were reported in 24 (6%) of 395 patients in the bimekizumab group (including those who switched from placebo at week 16) and 13 (8%) of 163 in the ustekinumab group.Bimekizumab was more efficacious than ustekinumab and placebo in the treatment of moderate to severe plaque psoriasis. The bimekizumab safety profile was consistent with that observed in previous studies.UCB Pharma.

Background Cumulative clinical improvement and speed of improvement are important to psoriasis patients. Objective Compare cumulative benefits of biologics over 12 to 16 weeks in the treatment of moderate to severe psoriasis. Methods A systematic literature review identified phase III trial data on Psoriasis Area and Severity Index (PASI) responses for biologics during 12 and 16 weeks of treatment. Cumulative clinical benefit, measured by the area under the curve for PASI ≥75% improvement (PASI 75), ≥90% improvement (PASI 90), and 100% improvement (PASI 100), was compared using the network meta-analysis and Bayesian methodology on the relative probability of achieving percentage of maximum area under the curve. Results Among biologics approved for psoriasis treatment, anti–interleukin-17 biologics demonstrated consistently greater cumulative clinical benefits on PASI 75, PASI 90, and PASI 100 over the 12- or 16-week period than anti–interleukin-23 and other biologics. For biologics with 12-week data, ixekizumab and brodalumab showed greater cumulative benefits for PASI 75, PASI 90, and PASI 100 than secukinumab, followed by guselkumab, infliximab, adalimumab, ustekinumab, and etanercept. Ixekizumab showed greater cumulative benefits than all other biologics reporting 16-week data. Limitations Recently approved biologics were not included. Conclusion Ixekizumab (at 12 weeks and 16 weeks) and brodalumab (at 12 weeks) had greater cumulative clinical benefit than all of other biologics studied.

Introduction Le deucravatinib (DEUC) est un nouvel inhibiteur oral selectif et allosterique de TYK2. Dans les essais de phase 3 POETYK PSO-1 ( NCT03624127 ) et PSO-2 ( NCT03611751 ) dans le psoriasis en plaques (PP) modere a severe, le DEUC a ete significativement plus efficace que le placebo et l’apremilast sur le PASI 75 et le sPGA 0/1. Cette analyse a evalue l’efficacite en fonction de sous-groupes predefinis selon les traitements anterieurs. Materiel et methodes Les patients (pts) atteints de PP modere a severe ont ete randomises 1:2:1 pour recevoir un placebo, DEUC 6 mg 1×/j ou apremilast 30 mg 2×/j. L’utilisation anterieure de traitement biologique ou systemique oral, a l’exception de l’apremilast, etait autorisee apres une periode de « wash out » appropriee avant le debut de l’etude. L’utilisation d’une phototherapie anterieure etait autorisee jusqu’a 4 semaines avant le debut de l’etude. Les co-criteres d’evaluation principale etaient le PASI 75 et le sPGA 0/1 a la semaine 16. Dans cette analyse, les reponses PASI 75 et sPGA 0/1 ont ete evaluees en fonction de l’utilisation anterieure de tout traitement systemique (biologique ou systemique oral), d’agents biologiques pour le psoriasis ou d’autres maladies inflammatoires (incluant les anticorps anti-IL-17, anti-IL-23 et anti-IL-12p40, les TNF inhibiteurs), et de la phototherapie (oui/non pour tous). Resultats Au total, 666 et 1020 pts ont ete respectivement randomises dans PSO-1 et PSO-2. Dans PSO-1, 62,8 % des pts avaient deja recu un traitement systemique anterieur, 38,9 % des pts (259/666) avaient deja recu un traitement biologique, 23,9 % (159/666) avaient deja recu un traitement oral systemique et aucun traitement biologique, et 35,9 % (239/666) une phototherapie. Dans PSO-2, 54,2 % des pts ont recu un traitement systemique anterieur, 32,1 % (327/1020) un traitement biologique anterieur, 22,2 % (226/1020) un traitement systemique oral anterieur et aucun traitement biologique, et 42,6 % (435/1020) une phototherapie. Dans l’ensemble des 2 essais, un nombre significativement plus eleve de pts recevant DEUC vs placebo et vs apremilast ont atteint un PASI 75 (PSO-1 : 58,7 % vs 12,7 % vs 35,1 %, p Discussion Dans les etudes POETYK PSO-1 et PSO-2, le DEUC a montre des taux de reponse PASI 75 et sPGA 0/1 superieurs a ceux du placebo et de l’apremilast, independamment du traitement anterieur recu (phototherapie, traitement systemique ou biologique).

High-throughput biology presents unique opportunities and challenges for dermatological research. Drawing on a small handful of exemplary studies, we review some of the major lessons of these new technologies. We caution against several common errors and introduce helpful statistical concepts that may be unfamiliar to researchers without experience in bioinformatics. We recommend specific software tools that can aid dermatologists at varying levels of computational literacy, including platforms with command line and graphical user interfaces. The future of dermatology lies in integrative research, in which clinicians, laboratory scientists, and data analysts come together to plan, execute, and publish their work in open forums that promote critical discussion and reproducibility. In this article, we offer guidelines that we hope will steer researchers toward best practices for this new and dynamic era of data intensive dermatology.

Introduction Le psoriasis est l’exemple parfait d’une maladie occasionnee par les Th17 ; des elements toujours plus nombreux suggerent que l’IL-17A au meme titre que l’IL-17F influencent son immunopathogenie. Le bimekizumab se lie selectivement a l’IL-17A et l’IL-17F et les neutralise. Materiel et methodes Dans BE VIVID (NCT03370133), une etude pivot de superiorite de phase 3, randomisee, en double aveugle, 567 patients presentant une forme moderee a severe de psoriasis ont ete randomises selon un rapport de 4/2/1 pour recevoir du bimekizumab (320 mg toutes les 4 semaines), de l’ustekinumab (45 ou 90 mg en fonction du poids a l’inclusion et a S4, puis toutes les 12 semaines) ou un placebo (toutes les 4 semaines jusqu’a S16, puis bimekizumab 320 mg toutes les 4 semaines). Les co-criteres principaux d’evaluation etaient le PASI90 et l’IGA 0/1 versus placebo a la Semaine 16. Les criteres d’evaluation secondaires incluaient le PASI100 a la Semaine 16 ; le PASI90, l’IGA 0/1 et le PASI100 a la Semaine 52 ; et la tolerance. Les donnees manquantes ont ete imputees comme absence de reponse. Resultats A S16, significativement plus de patients ont atteint le PASI90 et l’IGA 0/1 avec le bimekizumab (respectivement 85,0 % et 84,1 %) qu’avec l’ustekinumab (49,7 % et 53,4 %) ou le placebo (4,8 % et 4,8 % ; pour toutes les comparaisons, p Discussion Le bimekizumab a ete systematiquement superieur a l’ustekinumab et au placebo et a ete generalement bien tolere, avec un profil de tolerance coherent avec les etudes anterieures de phase 2, justifiant une nouvelle fois la double neutralisation selective de l’IL-17A et de l’IL-17F pour le traitement du psoriasis.

Introduction Dans le cadre d’un traitement d’entretien de 52 semaines chez des adultes atteints de psoriasis en plaques, une association fixe Cal/DB sous forme de mousse a ete etudiee versus placebo pour evaluer le delai avant la premiere rechute, le nombre de rechutes et le nombre de jours en remission. Il s’agit de la premiere etude montrant l’efficacite du traitement d’entretien a long terme du psoriasis en plaques avec un traitement topique bihebdomadaire. Materiel et methodes Etude de phase III, multicentrique, randomisee, controlee versus placebo visant a evaluer l’efficacite d’un traitement d’entretien avec une association fixe de calcipotriol a 0,005 % et de dipropionate de betamethasone a 0,064 % sous forme de mousse administree deux fois par semaine chez des patients atteints de psoriasis en plaques. Criteres d’eligibilite : ≥ 18 ans ; psoriasis du tronc et/ou des membres, touchant 2 a 30 % de la surface corporelle ; PGA ≥ 2 et indice modifie d’etendue et de gravite du psoriasis (mPASI) ≥ 2 a la visite 1. Les patients ont recu l’association Cal/DB une fois par jour pendant la phase en ouvert de 4 semaines. En cas de succes therapeutique (score « blanchi »/« quasi-blanchi » avec une amelioration ≥ 2 grades par rapport a l’inclusion), les patients etaient randomises en double aveugle selon un rapport 1 :1 Cal/DB ou placebo deux fois par semaine pendant 52 semaines. Critere d’evaluation principal : delai avant la premiere rechute (PGA ≥ 2). Criteres d’evaluation secondaires : nombre de rechutes ; proportion de jours en remission (PGA « blanchi »/« quasi-blanchi »). Resultats Au total, 650 patients ont ete inclus pour recevoir l’association Cal/DB ; 521 patients (80 %), en succes therapeutique a l’issue de la phase en ouvert ont ete randomises (Cal/DB, n = 256 ; groupe-controle, n = 265). Les caracteristiques de la pathologie etaient similaires entre les groupes. Parmi les patients randomises, 82 % avaient un score PGA « modere » a l’inclusion ; 251 (46,1 %) ont termine l’etude. Le delai median avant la premiere rechute etait de 56 jours avec l’association Cal/DB, contre 30 jours avec le placebo. Le risque de premiere rechute etait reduit de 43 % avec l’association Cal/DB par rapport au placebo (HR, 0,57 ; IC a 95 %, 0,47–0,69 ; p Discussion Cette etude montre l’efficacite d’un traitement d’entretien a long terme du psoriasis avec un traitement topique en application bihebdomadaire.

The identification of disease alleles underlying human autoinflammatory diseases can provide important insights into the mechanisms that maintain neutrophil homeostasis. Here, we focused our attention on generalized pustular psoriasis (GPP), a potentially life-threatening disorder presenting with cutaneous and systemic neutrophilia. Following the whole-exome sequencing of 19 unrelated affected individuals, we identified a subject harboring a homozygous splice-site mutation (c.2031-2A>C) in MPO. This encodes myeloperoxidase, an essential component of neutrophil azurophil granules. MPO screening in conditions phenotypically related to GPP uncovered further disease alleles in one subject with acral pustular psoriasis (c.2031-2A>C;c.2031-2A>C) and in two individuals with acute generalized exanthematous pustulosis (c.1705C>T;c.2031-2A>C and c.1552_1565del;c.1552_1565del). A subsequent analysis of UK Biobank data demonstrated that the c.2031-2A>C and c.1705C>T (p.Arg569Trp) disease alleles were also associated with increased neutrophil abundance in the general population (p = 5.1 × 10-6 and p = 3.6 × 10-5, respectively). The same applied to three further deleterious variants that had been genotyped in the cohort, with two alleles (c.995C>T [p.Ala332Val] and c.752T>C [p.Met251Thr]) yielding p values < 10-10. Finally, treatment of healthy neutrophils with an MPO inhibitor (4-Aminobenzoic acid hydrazide) increased cell viability and delayed apoptosis, highlighting a mechanism whereby MPO mutations affect granulocyte numbers. These findings identify MPO as a genetic determinant of pustular skin disease and neutrophil abundance. Given the recent interest in the development of MPO antagonists for the treatment of neurodegenerative disease, our results also suggest that the pro-inflammatory effects of these agents should be closely monitored.

A comprehensive evaluation of the risk of serious infections in biologic therapies for psoriasis is lacking. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) and prospective cohort studies reporting serious infections in people taking any licensed biologic therapy for psoriasis compared with those taking placebo, nonbiologic therapy, or other biologic therapies. The quality of the studies was assessed using Grading of Recommendations Assessment, Development and Evaluation criteria. No significant heterogeneity was detected in data from 32 RCTs (n = 13,359 participants) and one cohort study (n = 4,993 participants). In adults, low- to very-low-quality RCT data showed no significant difference between any biologic therapy and placebo at weeks 12–16 (overall pooled Peto odds ratio = 0.71, 95% confidence interval = 0.36–1.41) and weeks 20–30 (odds ratio = 2.27, 95% confidence interval = 0.45–11.49). No significant differences were found in any of the other comparisons in underpowered RCT data. Prospective cohort study data of low quality suggests that only adalimumab (adjusted hazard ratio [adjHR] = 2.52, 95% confidence interval = 1.47–4.32) was associated with a significantly higher risk of serious infection compared with retinoid and/or phototherapy in adults. No association between biologic therapies and serious infections in patients with psoriasis who were eligible for RCTs was detected. Further observational studies are needed to inform the uncertainty around this risk in the real world.

Although genome-wide association studies have revealed important insights into the global genetic basis of psoriasis, the findings require further investigation. At present, the known genetic risk loci are largely uncharacterized in terms of the variant or gene responsible for the association, the biological pathway involved, and the main cell type driving the pathology. This review primarily focuses on current approaches toward gaining a complete understanding of how these known genetic loci contribute to an increased disease risk in psoriasis.

Introduction Dans le cadre d’un traitement d’entretien de 52 semaines chez des patients atteints de psoriasis en plaques, une etude sur l’association fixe de calcipotriol a 0,005 % (Cal) et de dipropionate de betamethasone a 0,064 % (DB) sous forme de mousse a evalue l’efficacite et la tolerance de cette association. Materiel et methodes Etude de phase III, multicentrique, randomisee, controlee versus placebo evaluant l’efficacite et la tolerance d’un traitement d’entretien avec l’association Cal/DB 2X par semaine. Criteres d’eligibilite : ≥ 18 ans ; psoriasis du tronc et/ou des membres, touchant 2–30 % de SC ; un PGA ≥ 2 et un mPASI ≥ 2 a la visite 1. Les patients ont recu l’association Cal/DB 1x jour pendant la phase en ouvert de 4 semaines. En cas de succes therapeutique (PGA Resultats Dans la phase en ouvert, 521 patients etaient en succes therapeutique (Cal/DB, n = 256 ; placebo, n = 265). Le taux d’effets indesirables (EI) pour 100 patients-annees etait de 165,1 pour Cal/DB vs 156,1 pour le placebo. Le taux d’EI graves pour 100 patients-annees etait faible et comparable dans les deux groupes (Cal/DB, 8,2 ; placebo, 7,8), tout comme le taux d’EI lies au traitement (Cal/DB, 2,7 ; placebo, 4,5). Deux EI ont ete juges lies a l’utilisation prolongee de corticosteroides. Trois patients (Cal/DB, 2 [0,7 %] ; placebo, 1 [0,4 %]) ont eu des EI necessitant l’arret du traitement. Six patients du groupe Cal/DB et sept du groupe placebo ont presente un effet rebond dans les deux mois suivant l’entree dans la phase d’entretien. Effet rebond quatre fois plus probable avec le placebo (n = 17) qu’avec le Cal/DB (n = 4) apres une rechute. L’analyse en sous-groupes n’a pas mis en evidence d’effet cliniquement significatif sur le metabolisme du calcium ou l’axe HHS. Discussion L’association fixe Cal/DB sous forme de mousse a ete bien toleree dans le traitement d’entretien a long terme sur 52 semaines des patients atteints de psoriasis en plaques.

Introduction Secukinumab (SEC), anticorps monoclonal humain neutralisant selectivement l’IL-17A, est efficace dans le traitement du psoriasis en plaques modere a severe et du rhumatisme psoriasique. Les donnees des effets sur la grossesse d’un traitement du psoriasis par biotherapie sont peu nombreuses. Bien que les etudes sur l’animal ne montrent pas d’effet deletere sur le developpement embryofœtal, l’accouchement ou le developpement postnatal, les femmes enceintes etaient exclues des etudes de developpement clinique du SEC. Les protocoles d’etudes exigeaient l’utilisation de contraceptifs efficaces chez les femmes en âge de procreer. En cas de survenue d’une grossesse au cours d’un essai clinique, la patiente devait arreter le traitement de l’etude. Nous rapportons ici les cas de grossesses connues, lorsque la patiente ou son partenaire avait recu SEC, cas issus de la base de donnees de tolerance de Novartis. Materiel et methodes La base de donnees [essais cliniques et postcommercialisation (PC)] a ete analysee et tous les cas de grossesse avec une exposition maternelle (EM) ou paternelle (EP) a SEC ont ete inclus dans cette analyse (analyse arretee au 25/12/2015). Resultats L’exposition a SEC est estimee a plus de 21 500 patientes–annees. Dans tous les cas, SEC etait interrompu ou arrete des confirmation de la grossesse, dans la plupart des cas dans les premieres semaines du 1er trimestre. Parmi les grossesses confirmees, 63 ont eu lieu lors d’essais cliniques, 11 en PC et 10 ont ete rapportees spontanement. Soixante-six correspondaient a une EM et 18 a une EP. Les 15 EM arrivees a terme ont abouti a la naissance de nouveau-nes vivants et sans malformation congenitale, 11 grossesses etaient toujours en cours. Dans 32 cas d’EM, une interruption de grossesse etait programmee ou les informations etaient incompletes. Un avortement spontane est survenu dans 8 cas, tous lors du premier trimestre ; des antecedents de fausse couche ou mort neonatale ou des facteurs de risque potentiel (infection ou traitement concomitants) etant presents dans 6 cas. Les EP ont donne le meme profil de resultats que les EM. Parmi les grossesses menees a terme, toutes ont conduit a la naissance de nouveau-nes vivants sans anomalie congenitale. Discussion Les donnees sur les grossesses en cas d’exposition a SEC ont montre que toutes celles menees a terme ont conduit a la naissance de nouveau-nes vivants sans anomalie congenitale. Le taux d’avortement spontane se trouve dans l’intervalle attendu, tous s’etant produits lors du 1er trimestre et la majorite etant associee a d’autres facteurs de risque potentiels. Conclusion Ces resultats sont rassurants car ils ne montrent aucune evidence de teratogenicite ou de risque pour le fœtus avec SEC. Cependant, en l’absence de donnees pour certaines grossesses, la securite d’emploi de SEC pendant la grossesse necessite des etudes supplementaires.

The future management of psoriasis will depend on a number of distinct but ultimately inter-related strands of evidence, these are: (i) the interplay of genes and environment and the characterisation of psoriasis phenotypes; (ii) the role of pharmacogenetics in personalised healthcare; (iii) the translation of basic scientific discovery of relevant immune and angiogenic pathways into targeted biologic and small molecule therapies; and (iv) the recognition that the management of any chronic disease is enhanced by an understanding of psychosocial issues. A reductionist approach to development of new therapies will be paramount but serendipity and the prepared mind will contribute, as they have always done.

Abbreviations: GWAS, genome-wide association study; IL-23R, IL-23-receptor; SNP, single nucleotide polymorphism.