Introduction Le risankizumab (RZB) est un anti-IL-23 indiqué dans le traitement du psoriasis (PsO) en plaques modéré à sévère, du rhumatisme psoriasique et de la maladie de Crohn. L’étude en cours à 3ans VALUE évalue la durabilité de réponse à long terme en vie réelle avec le RZB versus autres biothérapies indiqués dans le traitement du PsO modéré à sévère. L’objectif de cette analyse intermédiaire à 148 semaines est de déterminer en vie réelle la durabilité de la réponse au RZB versus autres biothérapies (AutresBioT). Matériel et méthodes VALUE (NCT03982394), étude observationnelle prospective internationale post-AMM, a inclus des patients (≥18ans) atteints de PsO modéré à sévère traités par RZB ou AutresBioT approuvées (randomisation 2:1). L’inclusion des patients n’a eu aucune incidence sur les décisions thérapeutiques. Les critères d’évaluation de l’efficacité sont le PASI absolu, le DLQI la proportion de patients atteignant PASI 90 et PASI 100, le score TSQM ainsi que les changements de traitement. Les résultats (gel de la base le 7/12/2023) sont rapportés par méthode d’imputation en non-réponse modifiée (mNRI) pour laquelle les patients ayant switché ou arrêté leur biothérapie initiale en raison de manque d’efficacité ou d’intolérance ont été considéré comme en échec thérapeutique. Un appariement de 1:1 sur score de propension (PSM) a été réalisé afin de tenir compte du déséquilibre entre les groupes. Les valeurs nominales p sont présentées. Résultats Les caractéristiques à l’inclusion étaient comparables pour chacun des groupes (RZB, n=1765-AutresBioT, n=874). Le groupe RZB a inclus plus de patients avec un score PASI élevé à l’inclusion (15,0 vs 13,9 ; p=0,004), ayant des antécédents de rhumatisme psoriasique (259 [14,7 %] vs 233 [26,7 %]; p<0,0001) et bio-expérimentés (870 [49,3 %] vs 324 [37,1 %]; p<0,0001). Des proportions significativement plus élevées de patients atteignant PASI 90 à la semaine 16 (S16) et maintenant la réponse jusqu’à la semaine 148 (S148) étaient observées dans le groupe RZB versus le groupe AutresBioT (45,4 vs 29,6 %; p=0,0002). Significativement moins de patients du groupe RZB ont changé de traitement versus le groupe AutresBioT(10,9 vs 24,2 %; p<0,0001). Une proportion significativement plus élevée de patients ont atteint un score PASI 90 (67,2 vs 45,3 %; p<0,0001) et PASI 100 (55,2 vs 34,6 %; p<0,0001) dans le groupe RZB versus le groupe AutresBioT. Le score DLQI pour le groupe RZB était significativement moins élevé versus le groupe AutresBioT (2,5 vs 5,2; p<0,0001). Des scores TSQM de satisfaction globale significativement plus élevés ont été rapportés pour le groupe RZB versus le groupe AutresBioT (86,1 vs 75,5; p<0,0001). La tolérance du RZB était semblable aux études précédentes. Conclusion Cette analyse de l’étude VALUE montre une réponse clinique plus durable chez les patients traités par RZB par rapport aux patients traités par AutresBioT en vie réelle. Cette étude est toujours en cours et la totalité des patients n’ont pas encore atteint la S148.

Summary Background Fumaric acid esters (FAEs; Fumaderm®) are the most frequently prescribed first-line systemic treatment for moderate-to-severe plaque psoriasis in Germany. Risankizumab (Skyrizi®) is a humanized IgG1 monoclonal antibody that specifically binds to the p19 subunit of interleukin 23. Objectives To compare risankizumab treatment to FAEs in patients with psoriasis. Methods This phase III randomized, active-controlled, open-label study with blinded assessment of efficacy was conducted in Germany. Patients were randomized (1 : 1) to subcutaneous risankizumab 150 mg (weeks 0, 4 and 16) or oral FAEs at increasing doses from 30 mg daily (week 0) up to 720 mg daily (weeks 8–24). Enrolled patients were adults naïve to and candidates for systemic therapy, with chronic moderate-to-severe plaque psoriasis. Phototherapy was not allowed within 14 days before or during the study. Results Key efficacy endpoints were met at week 24 for risankizumab (n = 60) vs. FAEs (n = 60) (P < 0·001): achievement of a ≥ 90% improvement in Psoriasis Area and Severity Index (PASI; primary endpoint 83·3% vs. 10·0%), ≥ 100% improvement in PASI (50·0% vs. 5·0%), ≥ 75% improvement in PASI (98·3% vs. 33·3%), ≥ 50% improvement in PASI (100% vs. 53·3%) and a Static Physician’s Global Assessment of clear/almost clear (93·3% vs. 38·3%). The rates of gastrointestinal disorders, flushing, lymphopenia and headache were higher in the FAE group. One patient receiving risankizumab reported a serious infection (influenza, which required hospitalization). There were no malignancies, tuberculosis or opportunistic infections in either treatment arm. Conclusions Risankizumab was found to be superior to FAEs, providing earlier and greater improvement in psoriasis outcomes that persisted with continued treatment, and more favourable safety results, which is consistent with the known safety profile. No new safety signals for risankizumab or FAEs were observed.

BACKGROUND:Psoriasis is a chronic inflammatory skin disease requiring prolonged treatment. New biologic therapies require long-term evaluation to assess the durability of their efficacy and safety profiles over time.OBJECTIVES:To evaluate the long-term efficacy and safety of risankizumab (RZB) for the treatment of psoriasis.METHODS:LIMMitless is an ongoing, phase III, open-label extension study evaluating the long-term efficacy and safety of RZB in adults with moderate-to-severe plaque psoriasis following multiple phase II/III studies. This analysis assessed efficacy through 172 weeks of continuous RZB treatment by examining the proportion of patients achieving ≥ 90% or 100% improvement in Psoriasis Area and Severity Index (PASI 90 and PASI 100), static Physician's Global Assessment of clear or almost clear (sPGA 0/1) and Dermatology Life Quality Index of no effect on quality of life (DLQI 0/1). Safety was assessed by recording adverse events (AEs) through the data cutoff date. The study is registered at ClinicalTrials.gov (identifier: NCT03047395).RESULTS:Of 955 patients randomized to RZB 150 mg in the base studies, 897 patients continued into LIMMitless; 799 patients were still receiving treatment in LIMMitless at the time of data cutoff for this analysis. After 172 weeks of continuous RZB treatment, 85·5% of patients achieved PASI 90, 54·4% achieved PASI 100, 85·2% achieved sPGA 0/1, and 78·4% achieved DLQI 0/1 using modified nonresponder imputation. Rates of AEs leading to discontinuation and AEs of safety interest were low with long-term treatment and comparable with those identified in the base studies.CONCLUSIONS:Overall, long-term continuous RZB was well tolerated and showed high and durable efficacy over 172 weeks.

Background In a phase 3 clinical study, patients from Germany with moderate to severe psoriasis who were naive to systemic treatment and received risankizumab had greater and more rapid disease improvements compared with those who received fumaric acid esters (FAEs). Objective To evaluate patient-reported outcomes (PROs) in patients treated with risankizumab compared with FAEs. Methods Adult patients were randomized 1:1 to receive either risankizumab 150 mg subcutaneous injections at weeks 0, 4 and 16 or FAEs (Fumaderm(R)) provided according to the prescribing label. PRO secondary endpoints assessed were Psoriasis Symptom Scale (PSS), Dermatology Life Quality Index (DLQI), 36-Item Short Form Health Survey, version 2 (SF-36v2), Patient Benefit Index (PBI), Hospital Anxiety and Depression Scale (HADS), Patient Global Assessment (PtGA) and European Quality of Life 5 Dimensions 5 Level (EQ-5D-5L). PROs were assessed at weeks 0, 16 and 24. Results Sixty patients each were randomized to receive risankizumab or FAEs. A significant PSS improvement was observed with risankizumab vs. FAEs at weeks 16 and 24 for total and psoriasis-associated redness, itching and burning scores (P < 0.001). DLQI scores were significantly lower (reflecting better health-related quality of life) with risankizumab vs. FAEs, with least squares (LS) mean differences of -7.4 and -7.6 at weeks 16 and 24, respectively (both P < 0.001). Patients randomized to risankizumab also had larger improvements in SF-36 Physical and Mental Component Summary scores, HADS anxiety and depression scores, PtGA, and EQ-5D-5L index and visual analogue scale scores (all P <= 0.002) at weeks 16 and 24 compared with FAEs. PBI was significantly higher, indicating greater benefit, with risankizumab vs. FAEs, with an LS mean difference of 1.1 and 1.3 at weeks 16 and 24, respectively (both P < 0.001). Conclusions Risankizumab provides significant benefits over FAEs in improving PROs across several dimensions in patients with moderate to severe psoriasis.

BACKGROUND:Adalimumab (ADA) (Humira® , AbbVie Inc., U.S.A.) is approved by the European Medicines Agency for children aged ≥ 4 years with severe plaque psoriasis.OBJECTIVES:To evaluate the long-term efficacy and safety of ADA in children with severe plaque psoriasis.METHODS:Results are presented from the 52-week long-term extension (LTE) of the randomized, double-blind, double-dummy, phase III trial, in children with severe plaque psoriasis (results from prior periods have been published). Patients aged ≥ 4 and < 18 years were randomized 1 : 1 : 1 to ADA 0·8 mg kg-1 (40 mg maximum) or 0·4 mg kg-1 (20 mg maximum) every other week or to methotrexate (MTX) 0·1-0·4 mg kg-1 (25 mg maximum) weekly. The 16-week initial treatment (IT) period was followed by a 36-week withdrawal period and a 16-week retreatment period. Patients could enter the LTE at prespecified time points to receive ADA 0·8 mg kg-1 (blinded or open label) or ADA 0·4 mg kg-1 (blinded), or to remain off treatment. Efficacy is reported for patient groups according to doses received in the IT and LTE periods.RESULTS:Of the 114 patients randomized in the IT period, 108 entered the LTE (n = 36 in each group); 93 received ADA 0·8 mg kg-1 . Efficacy (≥ 75% improvement from baseline in Psoriasis Area and Severity Index) was maintained or improved from entry to the end of the LTE: MTX(IT)/ADA 0·8(LTE) 31-86% of patients; ADA 0·4(IT)/0·4 or 0·8(LTE) 28-47%; ADA 0·8(IT)/0·8(LTE) 50-72%. No serious infections occurred in the LTE.CONCLUSIONS:After 52 weeks of long-term ADA treatment in children aged 4-18 years with severe plaque psoriasis, disease severity was reduced and maintained or further improved, as demonstrated by efficacy outcomes. No new safety risks were identified. What's already known about this topic? The results from the first three periods of this phase III trial in children aged 4-18 years with severe plaque psoriasis suggest that adalimumab is a safe and efficacious treatment option in this population. What does this study add? This is the first study to evaluate long-term treatment of adalimumab in children with severe psoriasis, and the first to evaluate switching from methotrexate to adalimumab in this population.

Background In the Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT), elevated CRP was shown to predict radiographic progression.1 It is not known if CRP has a predictive role in the clinical response to adalimumab (ADA) treatment; however, it is known that obesity is related to subclinical inflammation as measured by CRP and that psoriatic arthritis (PsA) patients (pts) tend to be obese. Objectives To evaluate the effect of weight (wt) on clinical response in PsA pts treated with ADA Methods ADEPT was a 24-week (wk) double-blind, randomized, placebo-controlled trial in pts with PsA and inadequate response to NSAIDs. In this post hoc analysis, wt was categorized by quartiles (Q). For each wt and CRP category, wk 12 endpoints were analyzed: Clinical Disease Activity Index (CDAI), Psoriatic Arthritis Response Criteria (PsARC), Psoriasis Area & Severity Index (PASI) 75 response, and Health Assessment Questionnaire (HAQ). Multivariate analysis was done for wk 12 endpoints accounting for wt quartile and CRP category in the model. Results 309/313 pts enrolled had data available. Overall mean wt was 85.8 kg. Wt ranges (kg) per Q were: Q1=45.4–73.0, Q2=73.0–84.4, Q3=85.0–96.2, and Q4=97.0–156.0. CRP was elevated in 242/309 (78.3%). Pts with elevated CRP (%) in each wt Q was: Q1=67.5, Q2=75.3, Q3=85.2, Q4=84.6 (P=0.021). Wt was weakly correlated with CRP at baseline (BL) using non-parametric testing (Kendall Tau b r=0.131, P=0.006). Mean wt was higher in the elevated vs normal CRP group (87.6 kg vs 79.4 kg, P=0.0012). Mean wt (kg) in the elevated CRP group by Q was: Q1=64.6, Q2=78.7, Q3=90.7, Q4=109.7. BL disease activity (tender joint count, swollen joint count, physician and pt global assessment of disease activity, CDAI, PASI, HAQ) was slightly higher in the elevated CRP group. For all outcome measures (CDAI, PsARC (Figure), PASI75, and HAQ) treatment effect was in favor of ADA and no significant difference in treatment effect was observed across wt groups. In pts with both normal (n=67) and elevated (n=242) CRP statistically significant response in favor of ADA was observed for PASI75, with numerically superior but statistically nonsignficant results for CDAI, PsARC, and HAQ in pts with normal CRP. Wt group and CRP were not significant in the multivariate model. For CDAI, PsARC, and HAQ, treatment was statistically significant in favor of ADA regardless of wt or CRP. Sample sizes were too small to make meaningful conclusions for PASI. Conclusions The majority of PsA pts in ADEPT had an elevated CRP indicating a general inflammatory state. Overall, ADA-treated pts had superior response rates compared to PBO-treated pts regardless of wt or CRP category. A limitation of this assessment is that wt was used as a surrogate for BMI as pt height was not available. References Gladman DD et al. Arthritis Res Ther. 2010;12:R113. Acknowledgements AbbVie funded the study (NCT00646386), contributed to its design and was involved in the collection, analysis, and interpretation of the data, and in the writing, review, and approval of the publication. Medical writing support was provided by Kathleen V. Kastenholz, PharmD, MS, of AbbVie. Disclosure of Interest P. Mease Grant/research support from: AbbVie, Amgen, Biogen Idec, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Janssen Lilly, Merck, Merck Serono, Novartis, Novo Nordisk, Pfizer, Roche, UCB, and Vertex, Consultant for: AbbVie, Amgen, Biogen Idec, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Janssen Lilly, Merck, Merck Serono, Novartis, Novo Nordisk, Pfizer, Roche, UCB, and Vertex, Speakers bureau: AbbVie, Amgen, Biogen Idec, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Janssen Lilly, Merck, Merck Serono, Novartis, Novo Nordisk, Pfizer, Roche, UCB, and Vertex, D. Gladman Grant/research support from: AbbVie, Amgen, BMS, Celgene, Eli Lily, Janssen, Novartis, Pfizer, and UCB, Consultant for: AbbVie, Amgen, BMS, Celgene, Eli Lily, Janssen, Novartis, Pfizer, and UCB, C. Ritchlin Grant/research support from: Amgen, Janssen, Pfizer, and UCB, and consulting fees from AbbVie, Amgen, Janssen, Lilly, Pfizer, and UCB, R. Warren Grant/research support from: Abbvie, Amgen, Eli Lilly, GlaxoSmithKline, Janssen, Leo, Novartis, and Pfizer, Consultant for: Abbvie, Amgen, Eli Lilly, GlaxoSmithKline, Janssen, Leo, Novartis, and Pfizer, Speakers bureau: Abbvie, Amgen, Eli Lilly, GlaxoSmithKline, Janssen, Leo, Novartis, and Pfizer, S. Rubant Shareholder of: AbbVie, Employee of: AbbVie, Y. Li Shareholder of: AbbVie, Employee of: AbbVie, A. Dorr Shareholder of: AbbVie, Employee of: AbbVie, J. Anderson Shareholder of: AbbVie, Employee of: AbbVie

Mast cell numbers are markedly increased at sites of chronic inflammation. However, the underlying mechanisms of mast cell accumulation including mast cell progenitor trafficking remain to be identified in detail. Thus, the aim of this study was to identify the adhesion molecules involved in rolling, firm adhesion and transendothelial diapedesis of murine bone marrow-derived cultured mast cells (BMCMC) as a model for immature mast cells. We could show that BMCMCs exhibit in vivo rolling on skin vessel walls and strong adhesion to skin endothelial cells (ECs) in vitro under static and flow conditions. Interestingly, interaction of BMCMC with the EC adhesion molecules E- and P-selectin, vascular cell adhesion molecule-1 (VCAM-1) and platelet endothelial cell adhesion molecule-1 (PECAM-1) is required to mediate rolling and firm adhesion to ECs. The adhesion of BMCMCs to skin ECs is further enhanced by TNF, IL-4, IL-15 and vascular endothelial cell growth factor. Furthermore, BMCMCs exhibit directed and dose-dependent transmigration across an endothelial barrier, mediated by a PECAM-1-dependent mechanism. Our results demonstrate that BMCMCs can undergo a tightly regulated extravasation cascade consisting of rolling on and adhesion to endothelium and followed by directed diapedesis and reveal selectins, VCAM-1 and PECAM-1 as required adhesion molecules. These processes may contribute to mast cell accumulation in chronic inflammatory skin diseases and reveal opportunities to modulate peripheral tissue numbers of mast cells.

Luise Erpenbeck1,2; Simone Rubant3; Katja Hardt3; Sentot Santoso4; Wolf-Henning Boehncke3; Michael P. Schön1,2*; Ralf J. Ludwig2,5* 1Department of Dermatology, Venereology and Allergology, Georg August University, Göttingen, Germany; 2Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, Julius Maximilians University, Würzburg, Germany; 3Department of Dermatology, Clinic of the Johann Wolfgang Goethe University, Frankfurt am Main, Germany; 4Institute for Clinical Immunology and Transfusion Medicine, Justus-Liebig-University Giessen, Giessen, Germany; 5Department of Dermatology, University of Lübeck, Lübeck, Germany

The protective epithelial barrier in our skin undergoes constant regulation, whereby the balance between differentiation and proliferation of keratinocytes plays a major role. Impaired keratinocyte differentiation and proliferation are key elements in the pathophysiology of several important dermatological diseases, including atopic dermatitis and psoriasis. Ca2+ influx plays an essential role in this process presumably mediated by different transient receptor potential (TRP) channels. However, investigating their individual role was hampered by the lack of specific stimulators or inhibitors. Because we have recently identified hyperforin as a specific TRPC6 activator, we investigated the contribution of TRPC6 to keratinocyte differentiation and proliferation. Like the endogenous differentiation stimulus high extracellular Ca2+ concentration ([Ca2+](o)), hyperforin triggers differentiation in HaCaT cells and in primary cultures of human keratinocytes by inducing Ca2+ influx via TRPC6 channels and additional inhibition of proliferation. Knocking down TRPC6 channels prevents the induction of Ca2+- and hyperforin-induced differentiation. Importantly, TRPC6 activation is sufficient to induce keratinocyte differentiation similar to the physiological stimulus [Ca2+](o). Therefore, TRPC6 activation by hyperforin may represent a new innovative therapeutic strategy in skin disorders characterized by altered keratinocyte differentiation.

Selectin-mediated leukocyte rolling along the endothelium is of key importance for maintaining the cellular immune response. The anti-inflammatory activities of heparin have partly been related to inhibition of P-selectin binding. Heparin, however, suffers from its heterogeneous variable structure, the animal origin and multiple in vivo effects. As P-selectin is a promising target for anti-inflammatory approaches, we focused on P-selectin inhibition by other sulfated polysaccharides and compared them with six heparins. We examined 15 structurally defined semisynthetic sulfated glucans, non-animal-derived from the linear glucans phycarin, curdlan or pullulan. The derivatives gradually differ in their degree of sulfation, molecular weight, and glycosidic linkage. The inhibitory capacity was analysed in a parallel plate flow chamber, detecting the rolling of U937 cells on P-selectin layers. Unfractionated heparins displayed variabilities between different preparations. Considering fractionated heparins, exceeding of a minimal mass is essential for activity. Comparing the glucan sulfates, charge density is the most important parameter for P-selectin binding. Highly sulfated derivatives are excellent inhibitors, the reduced cell binding up to 16.2+/-6.4% strongly exceeded the heparin activities. Molecular weight is of minor effects, while glycosidic backbone linkage holds certain importance. To check the P-selectin inhibition in vivo, heparin and one phycarin sulfate were tested using intravital microscopy of microvasculature in mice. Both compounds significantly reduced the rolling fractions of activated platelets on endothelium as effective as a blocking P-selectin antibody. Our study indicates that semisynthetic glucan sulfates with optimal structures block P-selectin excellently and might become promising candidates for anti-inflammatory drugs to replace heparin for certain applications.

Pro-inflammatory chemokines and their receptors exhibit elementary functions in cell migration and in Th1-driven inflammatory conditions. One therapeutic strategy to prevent accumulation of pro-inflammatory immune cells is the use of specific chemokine receptor antagonists. An interesting and promising candidate in this context is the viral antagonist MIP-II (vMIP-II) that acts on a broad spectrum of chemokine receptors. To study the in vitro and in vivo effects of vMIP-II on pro-inflammatory chemokine receptor function, we further characterized an ovalbumin-specific murine central memory Th1IF12 clone by using RT-PCR, cDNA array and cytometry. Using in vitro chemotaxis assays we show that eukaryotically generated vMIP-II strongly inhibited migration of CCL2- or CCL5-stimulated Th1 IF12 cells. Using intravital microscopy, we observed that CCL5 induced rolling of Th1 cells in the ear vasculature of C57Bl/6 mice. Pre-treatment with vMIP-II significantly reduced CCL5-induced rolling of Th1 cells to basal levels, indicating, that vMIP-II is also active in vivo (proportion of rolling cells: 19.4 +/- 3.8%, 39.8 +/- 2.9% and 26.1 +/- 3.2%). In addition, investigating the anti-inflammatory action of vMIP-II in adoptive transfer of immunity and dinitrofluorobenzene-induced cutaneous hypersensitivity reaction using C57Bl/6 mice, we show a direct inhibitory effect of vMIP-II on the sensitization phase [Delta ear swelling 62 and 37 cm x 10(-3) for controls and vMIP-II treated mice (2.5 mg/kg), respectively] and effector phase (Delta ear swelling 14.8 and 3.6 cm x 10(-3) for controls and vMIP-II treated mice (2.5 mg/kg), respectively) of cutaneous hypersensitivity. These data indicate that vMIP-II is a promising agent to interfere with chronic inflammatory (skin) diseases.