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The protective epithelial barrier in our skin undergoes constant regulation, whereby the exact balance between differentiation and proliferation of keratinocytes plays a crucial role. Ca2+ influx is essential for this process presumably mediated by different transient receptor potential (TRP) channels. However, investigating their individual role in detail was hampered by the lack of specific stimulators or inhibitors. Since we have recently identified hyperforin as a specific TRPC6 activator, we investigated in the present study the contribution of TRPC6 to keratinocyte differentiation. Like the endogenous differentiation stimulus high extracellular Ca2+ concentration ([Ca2+]ex), hyperforin triggers differentiation in HaCaT cells and in primary cultures of human keratinocytes by inducing Ca2+ influx via TRPC6 channels. Hyperforin increases the mRNA levels of differentiation marker proteins such as Keratin 1, Keratin 10, Involucrin and Transglutaminase 1. Knocking down TRPC6 with siRNA technique and transfection with a dominant negative TRPC6 mutant prevents the induction of high [Ca2+]ex - and hyperforin-induced differentiation. The high [Ca2+]ex - and hyperforin-induced Ca2+ influx in TRPC6 inactivated cells is significantly lower than in untransfected cells. As a result, expression of differentiation markers is reduced in TRPC6 down knocked keratinocytes. The present study provides evidence for the fundamental role of TRPC6 in the regulation of keratinocyte differentiation. Therefore, TRPC6 activation by hyperforin may represent a new innovative therapeutic strategy in skin disorders characterized by altered keratinocyte differentiation, such as atopic dermatitis and psoriasis. [ABSTRACT FROM AUTHOR]

Introduction: Risankizumab has demonstrated superior efficacy compared to other psoriasis treatments, including secukinumab, adalimumab, and ustekinumab; switching to risankizumab from other psoriasis treatments has shown superior clinical and quality of life (QoL) outcomes. We evaluated the efficacy and safety of directly switching patients with moderate-to-severe plaque psoriasis and a suboptimal response to interleukin (IL)-17 inhibitors (secukinumab or ixekizumab) to risankizumab., Methods: This 52-week, phase 3b study enrolled patients (≥ 18 years) with moderate-to-severe plaque psoriasis who had previously been treated with the recommended dose of secukinumab or ixekizumab for ≥ 6 months but did not achieve an optimal response (static Physician's Global Assessment [sPGA] 2/3; body surface are [BSA] 3- < 10%). Patients received subcutaneous risankizumab (150 mg) without washout. The primary endpoint was the proportion of patients achieving sPGA of 0/1 at week 16. Secondary endpoints included sPGA 0/1 at week 52, sPGA 0, Dermatology Life Quality Index (DLQI) 0/1, and Psoriasis Symptoms Scale (PSS) 0 at weeks 16 and 52. Safety was monitored throughout the study., Results: The study included 244 patients. sPGA 0/1 was achieved by 57.4% and 62.3% at week 16 and 52. At week 16, sPGA 0, DLQI 0/1, and PSS 0 were achieved by 20.5%, 40.2%, and 20.9%, respectively. At week 52, these proportions increased to 27.1% for sPGA 0, 47.2% for DLQI 0/1, and 27.5% for PSS 0. Most frequently reported adverse events (reported in ≥ 5% of patients) in risankizumab-treated patients were COVID-19 infection (8.6%) and nasopharyngitis (5.7%). No new safety signals were observed., Conclusions: Directly switching to risankizumab improved outcomes and QoL in patients with moderate-to-severe psoriasis who had suboptimal responses to anti-IL-17 inhibitors (secukinumab or ixekizumab). The safety results are consistent with previously reported safety of risankizumab. This study supports the efficacy of risankizumab in patients previously treated with biologics, including IL-17 inhibitors, and suggests a direct switch to risankizumab for improved clinical outcomes and QoL., Clinical Trials: ClinicalTrials.gov identifier: NCT04102007., (© 2024. The Author(s).)

Background and Objectives: Flexible biologic therapy dosing regimens in psoriasis management are common, but data from routine care in Germany are scarce. This study evaluated treatment adjustments for biologic therapies commonly prescribed in Germany., Patients and Methods: Charts for up to 100 consecutive patients treated at 29 centers were reviewed. Data were extracted for adults (aged 18-65 years) with moderate-to-severe plaque psoriasis treated with adalimumab, guselkumab, ixekizumab, secukinumab, or ustekinumab for ≥ 36 weeks. The primary endpoint was time to first treatment adjustment. Secondary endpoints included frequency of and reasons for treatment adjustments. Time to treatment adjustment was analyzed using Kaplan-Meier methods., Results: Among 982 patients, 297 treatment adjustments in 240 (24.4%) patients were identified. The mean (median; interquartile range) time to first treatment adjustment (n = 223) was 8.4 (4.0; 2.0-12.0) months (secukinumab: 14.1 [10.0; 4.0-21.0], adalimumab: 11.0 [7.0; 3.0-14.5], ustekinumab: 11.0 [6.0; 2.0-16.0], ixekizumab: 5.8 [3.0; 2.0-8.5], guselkumab: 5.1 [3.0; 2.0-7.0]). The most frequent adjustment type was starting concomitant treatment(s) (10.4% of patients); insufficient skin effectiveness was the most frequent reason for adjustment., Conclusions: Biological treatment adjustments are frequent in moderate-to-severe psoriasis; flexible dosing regimens would support optimal management., (© 2024 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by Wiley‐VCH GmbH on behalf of Deutsche Dermatologische Gesellschaft.)

Psoriasis is a common, life-long skin disease with a significant negative health and societal impact. Data on rates of disease control and treatment strategies are lacking in Central and Eastern European countries. We aimed to describe the real-world disease severity, control, and treatment strategies for psoriasis in patients from Central and Eastern European countries. CRYSTAL (EUPAS36459) was a cross-sectional, retrospective study in adults (18-75 years) from Bulgaria, Estonia, Hungary, Latvia, Lithuania, Romania, and Russia. We enrolled patients with moderate-to-severe psoriasis receiving continuous systemic treatment for ≥24 weeks. We used the Psoriasis Area and Severity Index (PASI) to describe disease severity and the Dermatology Life Quality Index (DLQI) to assess quality of life (QoL) and collected other outcomes [psoriasis work productivity and activity impairment (WPAI-PSO), patient satisfaction] at enrollment. Analyses were descriptive. A total of 690 patients were included in the analyses. Median disease duration was 11.8 years. Current treatment was monotherapy for most patients (95.8%) with either biological (BIO group; 88.4%) or conventional (NON-BIO group; 7.4%) agents. Mean (± standard deviation) absolute PASI scores were 3.5 ± 5.7, 3.1 ± 5.3, and 6.6 ± 7.4 in the overall population, the BIO group, and the NON-BIO group, respectively. Among patients treated with monotherapy, absolute PASI scores ≤1, ≤3, and ≤5 were observed for 44.1%, 72.0%, and 82.6% of BIO patients and 21.6%, 33.3%, and 49.0% of NON-BIO patients. Mean DLQI total score was 3.3 ± 5.1; higher scores were noted for higher absolute PASI. The most impacted WPAI-PSO domain was presenteeism; for all domains, impact increased with increased absolute PASI. A total of 91.8% of BIO patients and 74.5% of NON-BIO patients were satisfied with the current treatment. We observed a better disease control in BIO than NON-BIO patients. However, around half of BIO patients did not reach clear skin status and reported an impact on QoL. An improvement in treatment strategies is still needed in Central and Eastern European countries to optimize outcomes of moderate-to-severe psoriasis., Competing Interests: LR reports honoraria for lectures and support for attending meetings from AbbVie. IH reports grants or contracts from Abbvie and Galderma; consulting fees from AbbVie and Janssen; honoraria for lectures and presentations at educational events from AbbVie, Janssen, and Novartis; and support for attending meetings and/or travel from AbbVie and Janssen. SV reports Investigator agreement and payment from AbbVie. AK reports honoraria for lectures and/or Investigator agreements from AbbVie, Eli Lilly, Pfizer, Regeneron, Janssen, and Leo Pharma. IB reports personal and institution payments from AbbVie. DM, SR, and TA are full-time employees of Abbvie and may hold AbbVie stock and/or stock options. MC reports consulting fees from AbbVie, Novartis Pharma, Eli Lilly, and Pfizer; honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Abbvie, Novartis Pharma, Eli Lilly, Pfizer, Janssen, UCB, Sun Pharma, Genesis Pharma, and Amring; payment for expert testimony from UCB and Amring; and support for attending meetings and/or travel from Terapia and for participation on Data Safety Monitoring or Advisory Board from UCB, Amring, and Novartis Pharma. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from AbbVie. The funder contributed to the design, participated in the collection, analysis, and interpretation of data, and in writing, reviewing, and approval of the final version., (Copyright © 2024 Raam, Hartmane, Valiukevičienė, Karamova, Telegdy, Botev, Marina, Rubant, Albuquerque and Constantin.)

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.

Introduction: Patients with moderate-to-severe plaque psoriasis who experience poor clinical outcomes, including patients with obesity or prior treatment, need improved treatment options. Risankizumab specifically inhibits interleukin 23 and has demonstrated superior efficacy in active-comparator studies in patients with moderate-to-severe plaque psoriasis. We compared the efficacy of risankizumab with that of secukinumab across patient subgroups., Methods: Subgroup analyses using data from the phase 3 IMMerge study (NCT03478787) were performed. Efficacy in adults with moderate-to-severe psoriasis treated with risankizumab 150 mg and secukinumab 300 mg was assessed as the proportion of patients who achieved ≥ 90% improvement in Psoriasis Area Severity Index (PASI 90) at week 52 across demographics and disease characteristics. Post hoc analyses evaluated the proportion of patients who achieved PASI 90 and the least-squares mean percent PASI improvement from baseline at week 52 by body weight and body mass index (BMI), PASI 90 by prior treatment, and clinical response [PASI 90, PASI 100, and/or static Physician's Global Assessment (sPGA) score of clear (0) or almost clear (1)] at week 16 and maintained particular response at week 52. Logistic regression analyses examined the effect of covariates (age, sex, BMI, baseline PASI, treatment) and potential interactions on PASI 90 at week 52., Results: More patients who received risankizumab (n = 164) compared with secukinumab (n = 163) achieved PASI 90 at week 52, regardless of demographics and disease characteristics (BMI, prior treatment, disease duration, and maintenance of clinical response at week 52). Improvements in PASI were greater in patients taking risankizumab than those taking secukinumab, regardless of weight or BMI. Results from logistic regression analysis showed treatment type had a significant impact on PASI 90 (risankizumab versus secukinumab, p < 0.0001)., Conclusion: Risankizumab showed consistently greater efficacy compared with secukinumab across different patient subgroups, and this was maintained through 52 weeks., Trial Registration: ClinicalTrials.gov identifier; NCT03478787., (© 2022. The Author(s).)

Background: ESPRIT 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., Objectives: Initial 5-year results are reported., Methods: Two 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., Results: Data 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., Limitations: Observational data are subject to outcome-reporting bias., Conclusion: No 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., (Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

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.

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. Ca(2+) 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 Ca(2+) concentration ([Ca(2+)](o)), hyperforin triggers differentiation in HaCaT cells and in primary cultures of human keratinocytes by inducing Ca(2+) influx via TRPC6 channels and additional inhibition of proliferation. Knocking down TRPC6 channels prevents the induction of Ca(2+)- and hyperforin-induced differentiation. Importantly, TRPC6 activation is sufficient to induce keratinocyte differentiation similar to the physiological stimulus [Ca(2+)](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.