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

Sex Bias in Pathogenesis of Autoimmune Neuroinflammation: Relevance for Dimethyl Fumarate Immunomodulatory/Anti-oxidant Action

In the present study, upon showing sexual dimorphism in dimethyl fumarate (DMF) efficacy to moderate the clinical severity of experimental autoimmune encephalomyelitis (EAE) in Dark Agouti rats, cellular and molecular substrate of this dimorphism was explored. In rats of both sexes, DMF administration from the day of immunization attenuated EAE severity, but this effect was more prominent in males leading to loss of the sexual dimorphism observed in vehicle-administered controls. Consistently, in male rats, DMF was more efficient in diminishing the number of CD4+ T lymphocytes infiltrating spinal cord (SC) and their reactivation, the number of IL-17+ T lymphocytes and particularly cellularity of their highly pathogenic IFN-gamma+GM-CSF+IL-17+ subset. This was linked with changes in SC CD11b+CD45+TCR alpha beta- microglia/proinflammatory monocyte progeny, substantiated in a more prominent increase in the frequency of anti-inflammatory phygocyting CD163+ cells and the cells expressing high surface levels of immunoregulatory CD83 molecule (associated with apoptotic cells phagocytosis and implicated in downregulation of CD4+ T lymphocyte reactivation) among CD11b+CD45+TCR alpha beta- cells in male rat SC. These changes were associated with greater increase in the nuclear factor (erythroid-derived 2)-like 2 expression in male rats administered with DMF. In accordance with the previous findings, DMF diminished reactive nitrogen and oxygen species generation and consistently, SC level of advanced oxidation protein products, to the greater extent in male rats. Overall, our study indicates sex-specificity in the sensitivity of DMF cellular and molecular targets and encourages sex-based clinical research to define significance of sex for action of therapeutic agents moderating autoimmune neuroinflammation-/oxidative stress-related nervous tissue damage

Porcine endogene Retroviren (PERVs): In vitro-Infektionsversuche und Etablierung von Methoden zum Nachweis der Virusintegration

Zum Nachweis der PERV-Integration im Genom verschiedener Schweinestämme und in infizierten humanen Zellen sollte die Southern Blot-Methode etabliert werden. Dazu wurden Sonden aus dem gag- und pol -Bereich generiert. Die Markierung dieser Sonden erfolgte zum einen nicht-radioaktiv mit Digoxigenin, zum anderen durch radioaktive Markierung mittels 32P. Test-Hybridisierungen mit kalten Sonden waren erfolgreich. Bei Hybridisierungsversuchen mit genomischer DNA aus PERV-produzierenden Schweinenierenzellen (PK-15) und PERV-infizierten humanen 293-Nierenzellen wurden nur wenige Banden detektiert. Da etwa 50 Proviren im Schweinegenom und mehrere Proviren in den verwendeten PERV-infizierten humanen Zellen vorkommen (Akiyoshi et al., 1998; Czauderna, 2000) und diese durch eine höhere Anzahl von Banden auf dem Blot erkennbar sein müssten, muß eine Verbesserung der Sensitivität der Methode erfolgen. Im zweiten Teil der Arbeit wurden In vitro-Infektionsversuche mit menschlichen Zellen durchgeführt, um potentielle Zielzellen zu erkennen und zu charakterisieren. Neben der menschlichen Nierenzelllinie (Takeuchi et al., 1998) konnten auch bereits primäre PBMC des Menschen (Denner, 1999; Wilson et al., 2000) und primäre vaskuläre Endothelzellen (Martin et al., 2000) mit PERV infiziert werden. In dieser Diplomarbeit konnten humane Milzzellen, Endothelzellen der Aorta und der Pulmonararterie produktiv mit PERV infiziert werden. Darüber hinaus erfolgte in dieser Arbeit erstmals die Infektion von Herzmuskelzellen mit PERV. Die Infektion von Muskelzellen ist bis zum jetzigen Zeitpunkt noch nicht beschrieben worden. Es konnte somit ein breites Spektrum von humanen Zellen sowie von Zellen anderer Spezies einschließlich nicht-humaner Primaten (Blusch et al., 2000; Specke, 2001) mit PERV infiziert werden. Die Expression in verschiedenen Zelltypen und verschiedenen Spezies ist dabei unterschiedlich. Weitere Infektionsstudien und die Entwicklung eines Tiermodells sind notwendig, um abzuschätzen, ob es zu einer Infektion und Gefährdung des Rezipienten durch Tumoren und / oder Immundefizienzen kommt und ob dabei eine Verbreitung der Viren auf Dritte möglich ist

Social Media Marketing Handbook for Art and Cultural Events

Events offer the opportunity to cities to create infrastructure, improve the image and revitalize the economy. Especially art and cultural events which reflect the mind, soul, and identity of the destination and their citizen. Offering more individuality to the participant experience, and a real possibility to those cities to differentiate themselves and improve community pride and destination image. Many of the organization producing this type of events are facing challenges because of the market development. Such as the growth of more organizations insight the same sector, which bring the increased need for finding financial resources for the different projects. Also, the competition for attracting new customer within the sector and other such as the entertainment industry. Another aspect of the market development is that customers are becoming more selected about their choices. Creating the shift from product oriented to customer-oriented market mindset. Many of these events and organization have a small structure and limited budget for function. As a result, they marketing range is restricted and in very close circles, limiting the possibility to anyone who will be interested in participating. As a solution, social media have the convenient tool for offering exciting information related to the organization or event. Give the possibility and tools to make art reachable to everyone. Also, increase brand awareness and help build a meaningful relationship with fans. This document is a product-oriented thesis, with the objective to gather and develop social media marketing strategy and tools on a practical handbook, to help promote cultural events. The thesis includes a theoretical framework comprised of three parts, event management, event marketing and marketing of cultural and art events. The empirical part of the thesis consists of the handbook creation process which includes four steps, interview, internet re-search and benchmarking, classifying the material and designing the handbook. The author had interviewed the different stakeholders taking part in this organization with the purpose to find why and how artist and promoters use social media marketing and participant expectation of the experience. Followed by internet research and benchmarking on the usage of the social media by art and cultural institutions as well as from expert in social media marketing strategy in other industries. From the results, the author selected the most critical point that can be helpful for art and cultural institution to take into consideration when planning the social media marketing camping. So, the last step was the design of the handbook and editing all the material gathered in templates and tables for practical use. The final step is the discussion and reflecting on the future of the book, and the process followed Handbook product as an attachment

Molekulare Wirkmechanismen rekombinant hergestellter Chemokinrezeptor-Antagonisten auf entzündungsrelevante Immunzellen

Im Rahmen dieser Arbeit wurde der nephritogene T-Helfer-1-Zellklon, IF12, hinsichtlich seines Chemokinrezeptorprofils auf RNA- und Proteinebene charakterisiert, um ein definiertes Zellmodell zu besitzen, welches für die anschließende Austestung von drei Chemokinrezeptor-Antagonisten geeignet ist. Dazu wurde die RNA von Mitogen-aktivierten und unstimulierten Th1-Zellen gewonnen und das Chemokinrezeptorprofil mittels RT-PCR und cDNA-Array untersucht. Das Ergebnis dieser Experimente zeigte eine konstitutive Expression der Rezeptoren CCR1, CCR2, CCR5-7, CXCR3, CXCR4 auf RNA-Ebene. Durch die Aktivierung der Th1 Zellen mit ConA wurde eine signifikant gesteigerte Expression von den Rezeptoren CCR4, CCR6 und CCR7 und eine deutliche Reduktion der Expression von CCR5 und CXCR3 induziert. Auf Proteinebene konnte die Oberflächenexpression der für die Antagonistenstudien wichtigen Chemokinrezeptoren CCR2, CCR5 und CXCR3 nachgewiesen werden. Hinsichtlich der gängigen Definition von T-Zell-Subtypen konnte der Th1IF12-Zellklon als central memory oder Gedächtnis-Zelltyp eingestuft werden (Sallusto et al., 1998). Dieser Zellklon wurde für die weiteren experimentellen Versuche verwendet. Weiterhin wurden drei Chemokinrezeptor-Antagonisten, eine N-terminal deletierte Form des Chemokins MCP-1/CCL2, MCP-1(1-8)del, virales MIP-II und eine N-terminal deletierte Variante des Chemokins I-TAC/CXCL11, I-TAC(1-3)del, in der methylotrophen Hefe Pichia pastoris exprimiert, durch Heparin-Affinitätschromatographie aufgereinigt und deren inhibitorische Wirkung auf die Th1-Zellen untersucht. Durch die Expression in Pichia pastoris konnten drei funktionell bioaktive Chemokinrezeptor-Antagonisten generiert wurden, die in der Lage waren, die spezifische Liganden-induzierte Th1-Chemotaxis Rezeptor-spezifisch zu inhibieren. Weiterhin konnte gezeigt werden, dass die Kombination von zwei Chemokinen (MCP-1/CCL2 und IP-10/CXCL10 oder I-TAC/CXCL11) die Th1-Migration signifikant steigerte und, dass eine deutliche Inhibition dieser gesteigerten Chemotaxis durch simultanen Einsatz von MCP-1(1-8)del und I-TAC(1-3)del erzielt wurde. Bei der Untersuchung zur Signalweiterleitung von CXCR3 wurde beobachtet, dass weder Pertussis-Toxin (PTX) noch AG490 einen Einfluss auf die I-TAC-induzierte Internalisierung hatte. Die I-TAC-vermittelte Chemotaxis konnte, wie erwartet durch PTX blockiert werden, wodurch die Signalvermittlung über Gi bestätigt wurde. AG490 führte überraschenderweise zu einer Steigerung der I-TAC-induzierten Chemotaxis. Die Effekte von PTX und AG490 wurden anschließend auf die I-TAC-induzierte Kalzium-Mobilisierung getestet und ergaben eine Blockierung des Kalziumsignals nach PTX-Behandlung, sowie ein verlängertes Kalziumsignal nach AG490-Behandlung. Beim Einsatz des Chemokinrezeptor-Antagonisten I-TAC(1-3)del im in vivo-Modell zur Untersuchung der Leukozytenwanderung im Mausohr (Intravitalmikroskopie, IVM) konnte beobachtet werden, dass ein durch IP-10/CXCL10-Stimulierung gesteigertes Rollverhalten der Th1-Zellen am Venenendothel durch anschließende Antagonisten-Behandlung signifikant inhibiert wurde. Zusammenfassend zeigt dies, dass die Expression der drei rekombinanten Chemokinrezeptor-Antagonisten, MCP-1(1-8)del, vMIP-II und I-TAC(1-3)del, in Pichia pastoris zu potenten und funktionell bioaktiven Proteinen führte, die ein viel versprechendes Werkzeug für die Behandlung Th1-vermittelter Entzündungskrankheiten darstellen

Sustained long-term efficacy and safety of adalimumab in paediatric patients with severe chronic plaque psoriasis from a randomized, double-blind, phase III study

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

Direct comparison of risankizumab and fumaric acid esters in systemic therapy-naïve patients with moderate-to-severe plaque psoriasis: a randomized controlled trial

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

Switching to risankizumab from ustekinumab or adalimumab in plaque psoriasis patients improves PASI and DLQI outcomes for sub-optimal responders

Background Psoriasis is often treated with biologic therapies. While many patients see improvement in their symptoms with treatment, some achieve only partial success. Objective and Methods In this post-hoc analysis we assess Psoriasis Area Severity Index (PASI) and Dermatology Life Quality Index (DLQI) results from patients who switched to RZB due to suboptimal results that originally received ADA (N = 53, IMMvent NCT02694523) or UST (N = 172, UltIMMa-1 [NCT02684370], UltIMMa-2 [NCT02684357]). Results For patients originally treated with ADA, after three doses of RZB, 83.3% of PASI 50 to <75 patients improved to PASI ≥75 and for PASI 75 to <90 patients, 77.1% improved to PASI ≥90. For patients originally treated with UST, after 7 doses of RZB, 86.8% of PASI <75 patients improved to PASI ≥75 and 75.5% of PASI 75 to ≤90 patients improved to PASI ≥90. No patients demonstrated worsening from their initial PASI group after switching. There were no significant safety events associated with switching patients to RZB without a washout period. Conclusion For patients with an inadequate or incomplete response to UST or ADA, switching to RZB improved PASI scores and DLQI for patients with moderate to severe plaque psoriasis with no significant safety risks