Treatment adjustment in biologic therapies for moderate-to-severe plaque psoriasis: a German retrospective chart review (TABU).

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.

Disease severity, treatment patterns, and quality of life in patients with moderate-to-severe psoriasis routinely managed with systemic treatment: results of the CRYSTAL observational study in Central and Eastern European countries.

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.

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.

Efficacy of Risankizumab versus Secukinumab in Patients with Moderate-to-Severe Psoriasis: Subgroup Analysis from the IMMerge Study.

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.

Patients with moderate-to-severe plaque psoriasis are often unable to achieve treatment success with currently available biologic therapies when they have other conditions, such as obesity, or have previous biologic therapy exposure and/or failure. We studied patients in the IMMerge phase 3 clinical trial (NCT03478787) to assess the efficacy of risankizumab compared with secukinumab for the treatment of plaque psoriasis and to determine risankizumab's ability to remain effective after 52 weeks of administration. In our analysis, we looked across patient subgroups including patient body weight, body mass index, previous use of biologic therapies, length of time patients had been living with their disease, and the durability of risankizumab efficacy at 52 weeks. Results from our analysis showed that patients had greater success with risankizumab compared with secukinumab in treating their plaque psoriasis, despite their age, sex, race, and disease characteristics, and that risankizumab remained effective in treating plaque psoriasis at week 52. Previously reported safety results from the IMMerge clinical trial showed that there were no new concerns regarding side effects for either risankizumab or secukinumab. Overall, these results support the use of risankizumab to treat patients, including those who have other conditions or may not have had success with other therapies in treating their plaque psoriasis.

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

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.

Immature mast cells exhibit rolling and adhesion to endothelial cells and subsequent diapedesis triggered by E- and P-selectin, VCAM-1 and PECAM-1.

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.

Specific TRPC6 channel activation, a novel approach to stimulate keratinocyte differentiation.

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.

Dimethylfumarate reduces leukocyte rolling in vivo through modulation of adhesion molecule expression.

Esters of fumaric acid have a long tradition in the treatment of psoriasis. Dimethylfumarate (DMF) is perceived as the main active substance. However, the molecular mechanisms of DMF action are not completely understood. Here, we investigate the effects of DMF on lymphocyte adhesion molecule expression in vitro and interactions with endothelial cells in vivo. DMF dose-dependently reduced superantigen-induced expression of CD25, human leukocyte antigen-DR, and cutaneous lymphocyte antigen by 27, 22, and 48% on CD3-positive cells, respectively. No change was observed for CD54, VLA-4, and P-selectin glycoprotein ligand-1. An enhancement of CD69 expression was noted (22%). DMF led to a significant reduction in binding of human peripheral blood mononuclear cells (PBMCs) to E-selectin (72%), P-selectin (36%), and vascular cell adhesion molecule-1 (33%) in vitro. Intravital microscopy of PBMCs in ear vasculature of wild-type and knockout mice showed that rolling was mainly P-selectin-dependent and could be reduced by 61% through DMF incubation. We provide early evidence that DMF affects adhesion molecule expression on human leukocytes and their rolling behavior in vivo, indicating that DMF directly affects the initial step of leukocyte extravasation.

Eukaryotic expression of the broad-spectrum chemokine receptor antagonist vMIP-II and its effects on T-cell function in vitro and in vivo.

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.

The influence of various structural parameters of semisynthetic sulfated polysaccharides on the P-selectin inhibitory capacity.

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.