Generalized pustular psoriasis: A global Delphi consensus on clinical course, diagnosis, treatment goals and disease management.

BACKGROUND: Generalized pustular psoriasis (GPP) is a rare and highly heterogeneous skin disease, characterized by flares of neutrophilic pustules and erythema. As a rare disease with few clinical studies and no standardized management approaches, there is a paucity of knowledge regarding GPP. OBJECTIVES: Conduct a Delphi panel study to identify current evidence and gain advanced insights into GPP. METHODS: A systematic literature review was used to identify published literature and develop statements categorized into four key domains: clinical course and flare definition; diagnosis; treatment goals; and holistic management. Statements were rated on a Likert scale by a panel of dermatologists in two rounds of online questionnaires; the threshold for consensus was agreement by ≥80%. RESULTS: Twenty-one panellists reached consensus on 70.9%, 61.8%, 100.0% and 81.8% of statements in the 'clinical course and flare definition', 'diagnosis', 'treatment goals' and 'holistic management of GPP' domains, respectively. There was clear consensus on GPP being phenotypically, genetically and immunologically distinct from plaque psoriasis. Clinical course is highly variable, with an extensive range of complications. Clinical and histologic features supporting GPP diagnosis reached high levels of agreement, and although laboratory evaluations were considered helpful for diagnosis and monitoring disease severity, there was uncertainty around the value of individual tests. All acute and long-term treatment goals reached consensus, including rapid and sustained clearance of pustules, erythema, scaling and crust, clearance of skin lesions and prevention of new flares. Potential triggers, associated comorbidities and differential diagnoses achieved low rates of consensus, indicating that further evidence is needed. CONCLUSIONS: Global consensus between dermatologists was reached on clinically meaningful goals for GPP treatment, on key features of GPP flares and on approaches for assessing disease severity and multidisciplinary management of patients. On this basis, we present a management algorithm for patients with GPP for use in clinical practice.

Evaluation of the effectiveness of risk minimization measures for trimetazidine: A cross sectional joint PASS survey among physicians in selected European countries.

PURPOSE: In 2012, the Committee for Medicinal Products for Human Use (CHMP) restricted prescription of trimetazidine (TMZ) to "add-on therapy for patients with stable angina pectoris who are inadequately controlled by or intolerant to first-line therapies." TMZ was no longer indicated for ophthalmology and otolaryngology. Risk minimization measure (RMM) was communicated to physicians. The survey presented here evaluated effectiveness of the RMM and assessed physicians knowledge and compliance with RMM. It also analyzed actual prescribing pattern of TMZ. METHODS: A cross sectional, web-based survey was developed and conducted among prescribing physicians of TMZ across 12 European countries. Physicians' samples were weighted to account for the actual proportion of specialties within and across countries. RESULTS: Using weighted samples, data from 1123 physicians and 8332 prescriptions were analyzed. Most (74.0%) of the physicians assumed stable angina pectoris to be an indication for TMZ. Three quarter of (75.7%) of these physicians were aware of the approved indication. Vertigo (62.1%), tinnitus (42.5%), declined visual acuity, and visual field disturbances (45.1%) were also presumed to be approved indications for TMZ, and physicians actually prescribed for these indications. Only 29.8% of the physicians remembered receiving RMM communications regarding TMZ. Most (90.5%) of the physicians expressed their interest to know and comply with the safety communications. Of all prescriptions, 33.9% were issued for add-on therapy for patients with stable angina pectoris. CONCLUSIONS: RMM for TMZ prescription have been moderately effective. Improvement in physician's compliance with safety information of TMZ is necessary for patient's safety.

Patient satisfaction with ExtaviPro™ 30G, a new auto-injector for administering interferon ß-1b in multiple sclerosis: results from a real-world, observational EXCHANGE study.

BACKGROUND: Patients with multiple sclerosis (MS) receiving long-term, subcutaneous interferon ß-1b (IFN ß-1b; Extavia®) often experience injection-site reactions and injection-site pain, which together with other side-effects (such as flu-like symptoms) result in suboptimal treatment compliance/adherence. The EXCHANGE study evaluated patient satisfaction with IFN ß-1b treatment, administered using ExtaviPro™ 30G, a new auto-injector, in a real-world setting. METHODS: This 26-week, open-label, prospective, non-interventional, observational, multi-country multi-centre study enrolled patients with MS who had been treated with IFN ß-1b or other disease-modifying therapies with a self-administered auto-injector for ≥3 months and who were planned to switch to IFN ß-1b treatment administered using ExtaviPro™ 30G as part of routine clinical care. Patient-reported outcomes included overall patient satisfaction (primary outcome) and satisfaction associated with treatment effectiveness, convenience and side-effects, assessed using Treatment Satisfaction Questionnaire for Medication (TSQM)-14. The changes in TSQM scores from baseline to Week 26 were reported. All data were analysed using SAS statistical software (version 9.4). RESULTS: Of the 336 patients enrolled, 324 were included in the analysis. At baseline, mean ± standard deviation (SD) age of patients was 41.8 ± 11.3 years and 68.2% were women. The mean ± SD of MS disease duration was 6.9 ± 6.6 years, and the majority of patients (94.1%) had relapsing-remitting MS. The mean ± SD of TSQM score for overall patient satisfaction at Week 26 was 75.6 ± 16.46 (baseline, 73.0 ± 17.14; p = 0.0342). The mean ± SD of TSQM subscale scores for patient satisfaction with effectiveness, side-effects and convenience were 75.0 ± 18.65 (baseline, 71.6 ± 19.45; p = 0.0356), 88.5 ± 18.98 (baseline, 82.7 ± 22.93; p = 0.0002) and 77.6 ± 16.72 (baseline, 71.1 ± 17.53; p < 0.0001), respectively. CONCLUSION: The results from this real-world study suggest that administering IFN ß-1b with the new ExtaviPro™ auto-injector significantly improves overall patient satisfaction, including satisfaction associated with effectiveness, side-effects and convenience in MS patients.

Patterns of Lisdexamfetamine Dimesylate Use in Children, Adolescents, and Adults with Attention-Deficit/Hyperactivity Disorder in Europe.

Objectives: Lisdexamfetamine dimesylate (LDX) is approved in some European countries for the second-line treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents when response to previous methylphenidate (MPH) treatment is considered clinically inadequate, and as a first-line treatment in adults. Limited evidence exists on the real-world use of LDX across Europe. This retrospective study evaluated LDX drug utilization patterns from eight European countries for up to 5 years. Methods: Data were collected from national registries (Denmark, Finland, Norway, Sweden), electronic medical records (Germany, Spain, United Kingdom), and prescription databases (Switzerland) in eight European countries. Patients were included if they were prescribed LDX at least once since the LDX launch date in each country. Demographic and clinical characteristics, and LDX prescription data included patient age and gender, a recorded diagnosis of ADHD, the number of prescriptions per participant, previous MPH prescription recorded, average daily dose, treatment persistence, discontinuation, and switching of medications. Results: Overall, information for 59,292 patients (437,272 LDX prescriptions) was analyzed. Most patients were male (58.1%-84.3%) and fewer than 1% were under 6 years of age. Extensive use of LDX in adults was observed in four countries (Denmark, Finland, Norway, and Sweden), including countries where LDX was not approved for this age group. Most patients had a recorded diagnosis of ADHD (61.9%-95.4%). The mean number of prescriptions per patient ranged from 5.4 to 10.0. At least 79.6% of patients with ADHD had a recorded previous MPH prescription. Mean duration of LDX exposure ranged from 233.1 to 410.8 days. The average daily dose of LDX was ≤70 mg/day for most patients (79.4%-99.7%). The 5-year discontinuation rate ranged from 22.8% to 70.6% and was below 40% for most countries. The proportion of patients switching from LDX to other medications was ≤33.8. Conclusions: This study provides the first long-term, real-world information related to LDX use by children, adolescents, and adults in Europe in the 5 years since its first launch in the region. Most LDX prescriptions fulfilled label requirements regarding a recorded diagnosis of ADHD before treatment initiation, previous MPH use, and an average daily dose of ≤70 mg/day. LDX was largely prescribed within the indicated age range, although adult use of LDX was high in some countries where LDX is not approved for this population.

Membrane type-1-matrix metalloproteinase expressed by prostate carcinoma cells cleaves human laminin-5 beta3 chain and induces cell migration.

Degradation of the extracellular matrix by proteolytic enzymes is a central aspect of physiological and pathologic tissue-remodeling processes such as trophoblastic implantation, wound healing, and tumor invasion. We have hypothesized that prostate adenocarcinoma cell invasion through the normal basal lamina is attributable in part to metalloproteinase-induced cleavage of laminin-5 (Ln-5) and enhanced motility of the cancer cells. We studied the role of membrane type-1-matrix metalloproteinase (MT1-MMP) expressed on the surface of prostate tumor cells in cleaving Ln-5 and enhancing the migration of prostate tumor cells. We also determined the nature of the MT1-MMP cleavage of human Ln-5 and how this altered Ln-5 changes the migration of prostate carcinoma cells. We found that human MT1-MMP cleaves purified human Ln-5 to an 80-kDa fragment. Mass spectrometry analyses of the 80-kDa cleaved product by trypsin and chymotrypsin gave 14 and 9 different peptide sequences, respectively, that were identical to the expected amino acid sequence of the Ln-5-beta3 chain. The recovered peptides represent 14.4% (trypsin) and 10.3% (chymotrypsin) of Ln-5-beta3 chain by amino acid count. Both trypsin and chymotrypsin digestion of MT1-MMP-cleaved product of Ln-5 did not show any other peptides that were identical to the other chains of Ln-5. Using a linear migration assay we found that the Ln-5 cleaved by MT1-MMP enhanced the migration of DU-145 prostate carcinoma cells by 2-fold compared with uncleaved Ln-5. The use of blocked antisense MT1-MMP oligonucleotides inhibited the migration of DU-145 cells on Ln-5. We also found that the prostate carcinoma cells expressing high levels of MT1-MMP, such as PC3N and PPC, demonstrated enhanced migration on human Ln-5-coated substrate, and this migration was inhibited using blocked antisense MT1-MMP oligonucleotides. In conclusion, this is a novel and important finding where we have shown that beta3-chain is cleaved by MT1-MMP, and this cleavage enhances migration of prostate cancer cells.

A Multicenter, Open-Label, Controlled Phase II Study to Evaluate Safety and Immunogenicity of MVA Smallpox Vaccine (IMVAMUNE) in 18-40 Year Old Subjects with Diagnosed Atopic Dermatitis.

BACKGROUND: Replicating smallpox vaccines can cause severe complications in individuals with atopic dermatitis (AD). Prior studies evaluating Modified Vaccinia Ankara virus (MVA), a non-replicating vaccine in humans, showed a favorable safety and immunogenicity profile in healthy volunteers. OBJECTIVE: This Phase II study compared the safety and immunogenicity of MVA enrolling groups of 350 subjects with AD (SCORAD ≤ 30) and 282 healthy subjects. METHODS: Subjects were vaccinated twice with MVA, each dose given subcutaneously 4 weeks apart. Adverse events, cardiac parameters, and the development of vaccinia virus humoral immune responses were monitored. RESULTS: The overall safety of the vaccine was similar in both groups. Adverse events affecting skin were experienced significantly more often in subjects with AD, but the majority of these events were mild to moderate in intensity. Seroconversion rates and geometric mean titers for total and neutralizing vaccinia-specific antibodies in the AD group were non-inferior compared to the healthy subjects. LIMITATIONS: The size of the study population limited the detection of serious adverse events occurring at a frequency less than 1%. CONCLUSION: MVA has a favorable safety profile and the ability to elicit vaccinia-specific immune responses in subjects with AD. TRIAL REGISTRATION: ClinicalTrials.gov NCT00316602.