Psoriasis increases the risk of cardiovascular (CV) disease. Secukinumab, a fully human monoclonal antibody against IL-17A, shows significant efficacy in psoriasis, but effects on CV markers are ...unknown. CARIMA (Evaluation of Cardiovascular Risk Markers in Psoriasis Patients Treated with Secukinumab) was a 52-week, randomized, double-blind, placebo-controlled, exploratory trial in patients with moderate to severe plaque psoriasis without clinical CV disease. Patients were randomly assigned to receive 300 mg or 150 mg secukinumab until week 52 or to receive placebo until week 12 and then 300 mg or 150 mg secukinumab until week 52. The primary outcome was endothelial function measured by flow-mediated dilation (FMD). Baseline FMD was significantly lower in psoriasis patients than healthy volunteers (4.4 ± 3.9% vs. 6.1 ± 3.3%, P = 0.01). At week 12, baseline-adjusted mean FMD was numerically higher in patients receiving secukinumab versus those receiving placebo, but this difference (300-mg group, +1.2%; 150-mg group, +0.76%; P = 0.223 and P = 0.403 by analysis of covariance) did not reach significance. At week 52, FMD increased across groups. FMD was significantly higher than baseline in patients receiving the label dose of 300 mg secukinumab for 52 weeks (+2.1%, 95% confidence interval = 0.8–3.3; P = 0.0022). Other relevant CV markers were unchanged. CARIMA indicates that secukinumab might have a beneficial effect on CV risk by improving the endothelial function of patients with plaque psoriasis.
Background: Secukinumab is a fully human monoclonal antibody that neutralizes interleukin-17A (IL-17A), a key cytokine involved in the development of psoriasis. Here, we characterized secukinumab ...treatment-responder profiles and identified baseline factors affecting response.
Methods: Pooled phase 3 data from moderate to severe plaque psoriasis patients treated with secukinumab for 16 weeks (FIXTURE NCT01358578, ERASURE NCT01365455, and CLEAR NCT02074982) were analyzed to characterize responder groups, identifying factors associated with treatment response, and to evaluate early response kinetics as a biomarker for treatment response. Etanercept and ustekinumab were evaluated as comparators.
Results: Patients treated with secukinumab 300 mg (n = 867), ustekinumab 45/90 mg (n = 318), and etanercept 50 mg (n = 298) were evaluated. For secukinumab 300 mg, more patients were in higher responder groups than etanercept and ustekinumab. In higher response groups, fewer patients had previous systemic or biologic treatment, metabolic syndrome, hypertension, diabetes, and fewer were current smokers. Mean body weight, waist circumference, and BMI decreased as response level increased. Early onset of response (PASI50 at Week 4 or 8) correlated with sustained efficacy at Week 16.
Conclusions: Baseline factors, including weight and cardiometabolic status, were associated with response to secukinumab. Early onset of response may indicate treatment efficacy later on.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Background Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, has shown superior efficacy to etanercept with similar safety in moderate to severe plaque psoriasis (FIXTURE study). ...Objective We sought to directly compare efficacy and safety of secukinumab versus ustekinumab. Methods In this 52-week, double-blind study ( NCT02074982 ), 676 subjects were randomized 1:1 to subcutaneous injection of secukinumab 300 mg or ustekinumab per label. Primary end point was 90% or more improvement from baseline Psoriasis Area and Severity Index (PASI) score (PASI 90) at week 16. Results Secukinumab (79.0%) was superior to ustekinumab (57.6%) as assessed by PASI 90 response at week 16 ( P < .0001). The 100% improvement from baseline PASI score at week 16 was also significantly greater with secukinumab (44.3%) than ustekinumab (28.4%) ( P < .0001). The 75% or more improvement from baseline PASI score at week 4 was superior for secukinumab (50.0%) versus ustekinumab (20.6%) ( P < .0001). Percentage of subjects with the Dermatology Life Quality Index score 0/1 (week 16) was significantly higher with secukinumab (71.9%) than ustekinumab (57.4%) ( P < .0001). The safety profile of secukinumab was comparable with ustekinumab and consistent with pivotal phase III secukinumab studies. Limitations The study was not placebo-controlled and of short-term duration. Conclusions Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate to severe psoriasis and improving health-related quality of life with a comparable safety profile over 16 weeks.
Background Secukinumab demonstrated superior efficacy to ustekinumab at week 4 and week 16 of the CLEAR study, with comparable safety, in subjects with moderate-to-severe plaque psoriasis. Objective ...To compare the efficacy and safety of secukinumab and ustekinumab use over 52 weeks. Methods Analysis of 52-week data from CLEAR, a randomized, double-blind, phase 3b study. Results Among 676 randomized subjects, secukinumab demonstrated superiority to ustekinumab at week 52 in the proportion of subjects with ≥90% improvement in Psoriasis Area and Severity Index (PASI 90) (76% vs 61% P < .0001); PASI 100 responses were 46% versus 36% ( P = .0103) and Investigator's Global Assessment responses of clear/almost clear skin were 80% versus 65% ( P < .0001). Subjects on secukinumab reported greater reductions in psoriasis-related pain, itching, and scaling, and greater improvement across all quality-of-life measures evaluated (Dermatology Life Quality Index DLQI, EuroQoL 5-Dimension Health Questionnaire, Work Productivity and Activity Impairment Questionnaire-Psoriasis, and Health Assessment Questionnaire-Disability Index). At week 52, 72% of subjects on secukinumab versus 59% on ustekinumab ( P = .0008) reported no impact of skin disease on their lives (DLQI 0/1 response). Safety and tolerability was comparable. Limitations There was no placebo arm. Conclusion In this head-to-head, double-blind study, secukinumab demonstrated sustained superior efficacy in comparison with ustekinumab in clearing skin through week 52, greater improvement in quality of life, and a favorable and comparable safety profile.
BackgroundGuselkumab is an interleukin (IL)-23 pathway blocker with proven efficacy in patients with moderate-to-severe plaque psoriasis. Early intervention with guselkumab may result in changes to ...the clinical disease course versus later intervention.Methods and analysisHere we present the rationale and design of a phase 3b, randomised, double-blind, multicentre study (GUIDE), comparing treatment effects of guselkumab in patients with short (≤2 years) or longer (>2 years) duration of plaque-type psoriasis, measured from first appearance of psoriatic plaques. Participants achieving skin clearance (Psoriasis Area and Severity Index (PASI)=0) by week 20 and maintaining complete clearance at week 28 visit (‘super-responders’ (SRe)) will be randomised to continue approved maintenance dosing every 8 weeks (q8w) versus an investigational maintenance dosing interval of 16 weeks (q16w) until week 68. Primary endpoint: proportion of participants in the q8w vs q16w arms with absolute PASI <3 at week 68. Participants with PASI <3 at week 68 will be withdrawn from guselkumab treatment for up to 48 weeks. Participants not achieving SRe criteria (non-SRe) will remain in the study with q8w guselkumab dosing through week 68. Additional to serum samples obtained from all patients, skin biopsies and whole-blood samples will be taken from SRe and non-SRe participants at various time points in optional substudies. Analyses include: genetics; immunophenotyping (fluorescence-activated cell sorting); gene and protein expression profiling; immunohistology. By merging clinical endpoints with mechanistic findings, this study aims to elucidate how IL-23 blockade with guselkumab can modify the disease course by altering molecular and cellular drivers that cause relapse after treatment withdrawal, particularly among SRe.Ethics and disseminationApproval obtained from ethics committee Medical Council Hamburg, Germany (PVN5925). GUIDE is compliant with the Declaration of Helsinki.Trial registration numberRegistered at ClinicalTrials.gov (NCT03818035). All primary endpoint results (prespecified analyses) will be submitted to peer-reviewed, international journals within 18 months after primary completion date.
Brodalumab, a recombinant fully human monoclonal immunoglobulin IgG2 antibody with high affinity to human interleukin (IL)-17RA, is approved for the treatment of moderate-to-severe plaque psoriasis. ...In controlled clinical trials, brodalumab 210 mg administered by subcutaneous injection at weeks 0, 1, and 2, then 210 mg every 2 weeks, produced a rapid onset and sustained clinical response. Consistently, >80% of patients achieved PASI-75 and efficacy was maintained for >2 years. The benefits are apparent soon after the start of therapy and are maintained in the long term. Such results, from the reviewed literature, support the findings from 4 'real world' cases in mainstream clinical practice which are reported here. Psoriatic plaques, including on the scalp, nails, soles and palms, were largely resolved, and quality of life improved markedly. Therapeutic success was achieved in patients naïve to biologics (2 cases) and in those responding inadequately to other biologics (2 cases). The high affinity of brodalumab to human IL-17RA blocks the biological activities of the pro-inflammatory cytokines IL-17A, IL-17C, IL-17E, IL-17F, and IL-17A/F heterodimer, resulting in inhibition of the inflammation and clinical symptoms associated with psoriasis. This mechanism of blocking multiple IL-17 family cytokines differs from that of other available biologics which selectively target some parts of the Th-17 axis and may account for the effectiveness of brodalumab in patients poorly responsive to other biologics, a feature which has also been shown where subgroup analysis has been undertaken in clinical trials. The drug is well tolerated during the normal 12-week induction phase and with prolonged treatment (52 to 120 weeks), as it was in the current case series.
Currently, in the treatment of moderate-to-severe psoriasis (PsO) there is a lack of evidence demonstrating optimal biologic treatment response with respect to disease duration. The aim of this ...post-hoc analysis, using real world data from the Psoriasis Study of Health Outcomes (PSoHO), is to provide evidence if early intervention with biologics is associated with better treatment outcomes and if there is any difference among drug classes or individual biologics.
For this post-hoc analysis patients were categorised into two subgroups according to shorter (≤2 years) or longer (>2 years) disease duration. Analysis was performed on anti-interleukin (IL)-17A cohort vs other biologics cohort, anti-IL-17A vs other drug classes, and pairwise comparisons of ixekizumab vs individual biologics, provided that the statistical models converged. Analysis investigated the association of disease duration with the proportion of patients achieving 100% improvement in Psoriasis Area Severity Index score (PASI 100) at week 12. Adjusted comparative analyses, reported as odds ratio (OR), were performed using Frequentist Model Averaging (FMA) for each cohort or treatments within each subcategory of the subgroups.
At week 12, anti-IL-17A and other biologics cohorts displayed minimal differences in numerical response rate for PASI 100 with respect to disease duration. The anti-IL-17A cohort showed a higher numerical PASI 100 response rate compared to the other biologic cohort irrespective of disease duration (≤2 years: 36.7% vs 21.8%; >2 years: 35.8% vs 21.9%).
Overall, the results do not clearly indicate that treating patients early is critical in achieving optimal patient outcomes. Furthermore, patients treated with ixekizumab show numerically higher response rates relative to other individual biologics irrespective of disease duration.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The formation of new lymphatic vessels provides an additional route for tumour cells to metastasize. Therefore, inhibiting lymphangiogenesis represents an interesting target in cancer therapy. First ...evidence suggests that histone deacetylase inhibitors (HDACi) may mediate part of their antitumor effects by interfering with lymphangiogenesis. However, the underlying mechanisms of HDACi induced anti-lymphangiogenic properties are not fully investigated so far and in part remain unknown.
Human lymphatic endothelial cells (LEC) were cultured in vitro and treated with or without HDACi. Effects of HDACi on proliferation and cell cycle progress were analysed by BrdU assay and flow cytometry. Apoptosis was measured by quantifying mono- and oligonucleosomes in the cytoplasmic fraction of cell lysates. In vitro lymphangiogenesis was investigated using the Matrigel short term lymphangiogenesis assay. The effects of TSA on cell cycle regulatory proteins and apoptosis-related proteins were examined by western blotting, immunofluorescence staining and semi-quantitative RT-PCR. Protein- and mRNA half-life of p21 were analysed by western blotting and quantitative RT-PCR. The activity of the p21 promoter was determined using a dual luciferase assay and DNA-binding activity of Sp1/3 was investigated using EMSA. Furthermore, siRNA assays were performed to analyse the role of p21 and p53 on TSA-mediated anti-lymphangiogenic effects.
We found that HDACi inhibited cell proliferation and that the pan-HDACi TSA induced G0/G1 arrest in LEC. Cell cycle arrest was accompanied by up-regulation of p21, p27 and p53. Additionally, we observed that p21 protein accumulated in cellular nuclei after treatment with TSA. Moreover, we found that p21 mRNA was significantly up-regulated by TSA, while the protein and mRNA half-life remained largely unaffected. The promoter activity of p21 was enhanced by TSA indicating a transcriptional mechanism. Subsequent EMSA analyses showed increased constitutive Sp1/3-dependent DNA binding in response to HDACi. We demonstrated that p53 was not required for TSA induced p21 expression and growth inhibition of LECs. Interestingly, siRNA-mediated p21 depletion almost completely reversed the anti-proliferative effects of TSA in LEC. In addition, TSA induced apoptosis by cytochrome c release contributed to activating caspases-9, -7 and -3 and downregulating the anti-apoptotic proteins cIAP-1 and -2.
In conclusion, we demonstrate that TSA - a pan-HDACi - has distinct anti-lymphangiogenic effects in primary human lymphatic endothelial cells by activating intrinsic apoptotic pathway and cell cycle arrest via p21-dependent pathways.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Moderate-to-severe plaque psoriasis can be treated very successfully with systemic therapies. Often the therapeutics must be injected subcutaneously. This prospective observational study aimed to ...compare the correct preparation and performance of subcutaneous injections in trained and untrained patients with plaque psoriasis.
We asked 110 patients (29.1% women, 70.9% men, injection system: 75.5% prefilled syringe, 24.5% autoinjector) to what extent they were trained for self-injection. While participants injected a sham injection with their current system, we evaluated the preparation, execution, and follow-up using a newly developed scoring system.
87.3% (n = 96) of the participants declared that they had been trained for self-injection. No statistically significant difference was observed between the trained and untrained participants in performing the injection correctly (p = .458). The most common mistakes were the wrong preparation and follow-up of the injection. A bifactorial rank-variance analysis showed a negative influence of the factor injection system (prefilled syringe) on the total score (p = .005).
We can indicate that patients with plaque psoriasis are well prepared for subcutaneous self-injection. Self-injection of systemic therapies is easy to perform, especially with patient-friendly systems, and does not require specialized training.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Acrodermatitis continua of Hallopeau (ACH) is a rare chronic inflammatory skin disease. Treatment is extremely challenging and mostly based on empirics as there is only scarce evidence from case ...reports and few small case series. In this retrospective study, patients with ACH treated at five university medical centers were analyzed according to patient and disease characteristics and treatment experience. We identified 39 patients with ACH with a mean age of 54.4 years at onset, of whom 22 (56.4%) were female. A total of 115 systemic treatment courses were analyzed with methotrexate as the most common therapy (27.0%). Overall, effectiveness of systemic treatments was low (excellent response rate: 14.8%). Among non‐biologics, excellent response was noted in 21.1% (4/19) of treatment courses with methotrexate, followed by acitretin (13.3%; 2/15). Among biologics, guselkumab (excellent response: 100%; 2/2), secukinumab (excellent response: 42.9%; 3/7) and adalimumab (excellent response: 20.0%; 2/10) were most efficacious. The median drug survival was 7.0 months and did not differ significantly between the subgroup of non‐biologic and biologic therapies. To our knowledge, this is the largest case series in ACH investigating patient characteristics and treatment outcomes. Based on our treatment experience, we suggest a treatment algorithm starting with acitretin or methotrexate as first‐line therapy, followed by biologics. Cyclosporin may be used for short‐term control. However, none of the applied systemic therapies yielded satisfying efficacy in our cohort. In patients with primary non‐response, switch of treatment should be evaluated timely on an individual basis, considering possible irreversible disease complications such as nail loss. More research with prospective design is needed to further evaluate traditional and also particularly newer antipsoriatic drugs in ACH.
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