Secukinumab maintains superiority over ustekinumab in clearing skin and improving quality of life in patients with moderate to severe plaque psoriasis: 52-week results from a double-blind phase 3b trial (CLARITY).

BACKGROUND: Secukinumab demonstrated superior efficacy over ustekinumab in the treatment of moderate to severe plaque psoriasis over 16 weeks in the CLARITY study and over 52 weeks in the CLEAR study. OBJECTIVE: To compare the efficacy and safety of secukinumab vs. ustekinumab over 52 weeks in CLARITY. METHODS: Analysis of 52-week data from CLARITY (NCT02826603), a phase 3b study in which patients were randomized to receive secukinumab 300 mg (n = 550) or ustekinumab 45/90 mg (n = 552) per label. RESULTS: At week 52, secukinumab was superior to ustekinumab in the proportion of patients who achieved ≥ 90% improvement in Psoriasis Area and Severity Index (73.2% vs. 59.8%; odds ratio [OR], 1.84 [95% CI, 1.41-2.41]; P < 0.0001), Investigator's Global Assessment modified 2011 responses of clear (0) or almost clear (1) skin (76.0% vs. 60.2%; OR, 2.12 [95% CI, 1.61-2.79]; P < 0.0001) and Dermatology Life Quality Index response of no effect (0/1) (69.9% vs. 61.2%; P = 0.0028). Proportions of patients with any adverse events were comparable between treatment arms. CONCLUSIONS: This second head-to-head study confirmed the superior efficacy of secukinumab over ustekinumab in skin clearance and quality of life through 52 weeks, with safety comparable to that reported in previous trials. Clinicaltrials.gov identifier: NCT02826603.

Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, exhibits low immunogenicity in psoriasis patients treated up to 5 years.

BACKGROUND: Secukinumab is a fully human monoclonal antibody that selectively neutralizes IL-17A, a key cytokine involved in psoriasis and psoriatic arthritis development, and has shown rapid and long-lasting efficacy and safety in the complete spectrum of psoriasis manifestations. Monoclonal antibody therapies may be associated with the production of treatment-emergent antidrug antibodies (TE-ADAs) that can affect drug pharmacokinetics, diminish clinical responses via inhibition of target binding or cause hypersensitivity reactions. Secukinumab exhibited minimal immunogenicity up to 52 weeks in patients with moderate-to-severe plaque psoriasis, as evidenced by TE-ADA in <1% patients. OBJECTIVE: To investigate the immunogenicity of secukinumab treatment up to 5 years in two phase 3 extension studies (NCT01640951 and NCT01365455) in patients with moderate-to-severe plaque psoriasis. METHODS: Immunogenicity was evaluated up to Week 268 (5 years). TE-ADAs were defined as positive antidrug antibody (ADA) signals detected in post-treatment samples from patients with negative baseline signals. Confirmed positive samples were further analysed for their neutralizing potential. RESULTS: In total, 1821 patients entered the extension studies. Among patients receiving secukinumab and evaluated for ADAs (n = 1636), 32 developed TE-ADA, which resulted in an incidence of new TE-ADA cases below 1% per year. Neutralizing antibodies were detected in 9/32 (28%) patients with TE-ADA. Half of ADA-positive cases were transient. Among pharmacokinetic samples measured at the times of immunogenicity determination (n = 9992), 544 (5.4%) had secukinumab concentrations higher than the drug tolerance level of 53.8 µg/mL. There was no effect of TE-ADA, including neutralizing antibodies, on efficacy, safety or pharmacokinetics of secukinumab. CONCLUSION: The yearly secukinumab immunogenicity incidence over 5 years of treatment was consistently below 1% in patients with moderate-to-severe plaque psoriasis. Any TE-ADAs, including neutralizing antibodies, were not associated with loss of secukinumab efficacy or with clinical concerns.

Five-year results from a phase 2 study of oral fingolimod in relapsing multiple sclerosis.

We present here results at 60 months (M), from the extension component of a phase 2, randomized, placebo-controlled, double-blind, six-month study evaluating oral fingolimod (1.25 mg or 5 mg daily) in relapsing multiple sclerosis. Placebo patients from the core study were re-randomized to fingolimod 1.25 mg or 5 mg in the extension. All patients received 1.25 mg fingolimod after the M24 visit. A total of 140/281 (49.8%) patients completed M60. Fingolimod treatment was associated with a low annualized relapse rate (0.2 relapses/ year), low MRI activity, and a modest rate of disability progression in those treated for five years. No new safety issues were reported.

Oral fingolimod (FTY720) in relapsing multiple sclerosis: impact on health-related quality of life in a phase II study.

BACKGROUND: Health-related quality of life (HRQoL) worsens with multiple sclerosis (MS) relapses and disease progression. Common symptoms including depression and fatigue may contribute to poor HRQoL. OBJECTIVES: To report exploratory analyses assessing the impact of fingolimod (FTY720) on HRQoL and depression in a phase II study of relapsing MS. METHODS: The Hamburg Quality of Life Questionnaire in MS (HAQUAMS) and Beck Depression Inventory second edition (BDI-II) scores were assessed during a 6-month, placebo-controlled study and optional extension. RESULTS: HAQUAMS total score improved with fingolimod and worsened with placebo. Mean score change from baseline to month 6 was -0.02 with fingolimod 1.25 mg (p < 0.05 versus placebo), -0.01 with fingolimod 5.0 mg and + 0.12 with placebo. Categorical data supported a clinically important effect of fingolimod on HRQoL. Fingolimod 1.25 mg was also beneficial over placebo in the fatigue/thinking HAQUAMS sub-domain (p < 0.05 versus placebo). Change in mean BDI-II scores from baseline to month 6 and the proportion of patients with BDI-II scores indicative of clinical depression favored fingolimod 1.25 mg over placebo (p < 0.05 for both). At month 4, mean BDI-II and HAQUAMS total scores appeared to be maintained in fingolimod-treated patients. CONCLUSION: Fingolimod 1.25 mg may improve HRQoL and depression at 6 months compared with placebo in patients with relapsing MS.

Recent and historical pollution legacy in high altitude Lake Marboré (Central Pyrenees): A record of mining and smelting since pre-Roman times in the Iberian Peninsula.

We have analyzed potential harmful trace elements (PHTE; Pb, Hg, Zn, As and Cu) on sediment cores retrieved from lake Marboré (LM) (2612 m a.s.l, 42°41'N; 0° 2'E). PHTE variability allowed us to reconstruct the timing and magnitude of trace metal pollutants fluxes over the last 3000 years in the Central Pyrenees. A statistical treatment of the dataset (PCA) enabled us to discern the depositional processes of PHTE, that reach the lake via direct atmospheric deposition. Indeed, the location of LM above the atmospheric boundary layer makes this lake an exceptional site to record the long-range transport of atmospheric pollutants in the free troposphere. Air masses back-trajectories analyses enabled us to understand the transport pathways of atmospheric pollutants while lead isotopic analyses contributed to evaluate the source areas of metal pollution in SW Europe during the Late Holocene. PHTE variability, shows a clear agreement with the main exploitation phases of metal resources in Southern Europe during the Pre-Industrial Period. We observed an abrupt lead enrichment from 20 to 375 yrs CE mostly associated to silver and lead mining and smelting practices in Southern Iberia during the Roman Empire. This geochemical data suggests that regional atmospheric metal pollution during the Roman times rivalled the Industrial Period. PHTE also increased during the High and Late Middle Ages (10-15th centuries) associated to a reactivation of mining and metallurgy activities in high altitude Pyrenean mining sites during climate amelioration phases. Atmospheric mercury deposition in the Lake Marboré record mostly reflects global emissions, particularly from Almadén mines (central Spain) and slightly fluctuates during the last three millennia with a significant increase during the last five centuries. Our findings reveal a strong mining-related pollution legacy in alpine lakes and watersheds that needs to be considered in management plans for mountain ecosystems as global warming and human pressure effects may contribute to their future degradation.

Constraints on dairy cattle productivity at the smallholder level in the Philippines.

Survey data on dairy cattle production were gathered in two sites [Site I (three-year survey) and Site II (two-year survey)] in Southern Luzon, Philippines. Crossbred (Holstein-Friesian x Sahiwal) dairy cows (n = 122) managed by smallholder farmers belonging to five primary cooperatives under the federation of dairy farmers, were monitored monthly for milk production, feed intake and availability, and reproduction and health status. The purpose of the survey was to identify constraints to productivity. The reproductive status of the cows was monitored by measuring milk and plasma progesterone concentrations by radioimmunoassay and rectal palpation of the ovaries. Plasma concentrations of selected metabolites [beta-hydroxybutyrate (BHB), inorganic phosphorus, albumin, globulin, urea] were also measured at one month before calving and at one month and 2-3 months postpartum, to determine if these could serve as biochemical indicators of nutritional stress. A long calving interval (CI = > 400 days) was identified as the major constraint to productivity of dairy cattle on smallholder farms. The three main problems related to this reproductive constraint were: (1) poor breeding management, in particular lack of accurate estrus detection; (2) repeat breeding, i.e. three or more services were required before conception; and (3) poor ovarian function, shown by some cows with lose progesterone levels. An important cause of these problems was undernutrition, particularly at critical periods of the cow's reproductive life, reflected in the slow recovery from loss in body weight and condition score during the early postpartum period and the increased plasma BHB values at peripartum period in some cows, indicative of negative energy balance, and the flat lactation profile. These findings are useful and relevant as a database in the development of an appropriate management scheme aimed toward improving dairy cattle production and productivity at smallholder level. It highlights the importance of estrus detection, good breeding management and the use of a practical strategic nutritional supplementation, particularly during stressful periods in the cows's reproductive life.

[Assessment of nutritional status at hospital admission: identification of patients with risk for malnutrition]. / Evaluación del estado nutricional al ingreso hospitalario: identificación de pacientes con riesgo de malnutrición.

Various studies of prevalence in our hospitals have detected large percentages of under-nourished patients in both medical and surgical wards. These groups of patients are not detected in clinical practice and are therefore untreated, leading to nutritional deterioration. The present paper studies the prevalence of the risk of malnutrition, using the Cardona risk assessment sheet as modified by Mager, in 134 patients between the 3rd and 5th day after admission to hospital. A chi-squared test was applied to allow comparison of quantitative and qualitative variables. We found 56.70% of patients risked under-nourishment (60% in medical wards and 50% in surgical wards). The variables which showed the best correlation with the risk of malnutrition were albumen (p < 0.01), weight loss (p < 0.001) and age (p < 0.005). The Hospital's Clinical Nutrition Committee must define the standard to be achieved regarding nutritional risk in order to ensure the quality offered to our patients in this regard.

[Impact of hospitalization on patients with nutrition status evaluation at admission]. / Influencia de la hospitalización en los pacientes evaluados nutricionalmente al ingreso.

Malnutrition (MN) continues to be an unacknowledged and underestimated problem in hospitals. It affects patients, by increasing complications, mean hospital stay (HS) and health-related risks. Such MN tends to be aggravated by hospitalization. Our purpose was to analyze the influence of hospitalization on the nutritional status of the patients studied. The following data were collected from 134 patients previously assessed for malnutrition risk between the 3rd and 5th day after admission: 1) during admission: type of diet, no of days with an absolute diet, use of protein supplements and artificial nutrients, onset of large-scale and small-scale complications, duration of HS, no of subsequent admissions and death; and 2) on discharge: serum albumin (SA) g/dl, total lymphocytes (TL)/ml. A statistical analysis was carried out using the chi 2 test, a Correlation test and ANOVA for a significance level of p < 0.05. It was possible to review 71.64% of the case histories and 61.45% were assessed. The following findings were reached: 1) the patients with weight loss on admission (WLA) had lower SA figures on discharge (p < 0.01) and a higher mortality rate (p < 0.001). 2) Absolute diet during HS led to a lengthening of admission time (p < 0.001). 3) Those patients with a severe risk of MN were the same ones who only received nutritional support (p < 0.001). 4) Patients who were re-admitted presented a worse nutritional status on discharge (p < 0.001). 5) An increase of 3.7 days in the HS in medical cases and 7.9 days more in surgical services, for those patients at risk of MN. 1. Low SA, TL and WLA figures are prognostic factors for hospital death. 2. Nutritional support was only used at severe levels of MN risk, so the HS was longer in these cases. 3. Patients with MN should be detected on arrival in order to avoid inherent health risks during hospitalization.

[Descriptive study of a serie of patients affected by progressive supranuclear palsy]. / Análisis descriptivo de una serie de pacientes afectados de parálisis supranuclear progresiva.

INTRODUCTION: Progressive supranuclear palsy is a neurodegenerative disorder affecting diverse neurologic systems. The actual treatment response is poor in most patients. OBJECTIVE: review of a long series of patients affected by PSP in several aspects. PATIENTS AND METHODS: A series of patients was reviewed by means of the register questionnaire of PSP in Spain (from PSP Disabling Rating Scale and Staging System). This is carried out on the patients when the diagnostic is done. It was achieved a descriptive of the patients, in several aspects, and an evaluation of the treatment in relation to the dose and the duration. RESULTS: In general, the age of diagnostic is 66 years, there is not neurological illness in the family, falls and disorders of gait are the most representative parameters. The neuroimage shows fronto temporal atrophy. The treatment response is poor, despite the dose and the duration. CONCLUSIONS: Our series confirms the typical dates of the illness an the poor response to treatment with L Dopa.

Oral fingolimod (FTY720) in multiple sclerosis: two-year results of a phase II extension study.

OBJECTIVE: To report the results of a 24-month extension of a phase II trial assessing the efficacy, safety, and tolerability of the once-daily oral sphingosine-1-phosphate receptor modulator, fingolimod (FTY720), in relapsing multiple sclerosis (MS). METHODS: In the randomized, double-blind, placebo-controlled core study, 281 patients received placebo or FTY720, 1.25 or 5.0 mg/day, for 6 months. During the subsequent dose-blinded extension, patients assigned to placebo were re-randomized to either dose of FTY720; those originally assigned to FTY720 continued at the same dose. Patients receiving FTY720 5.0 mg were switched to 1.25 mg during the month 15 to month 24 study visits. RESULTS: Of 281 patients randomized in the core study, 250 (89%) entered the extension phase, and 189 (75.6%) received treatment for 24 months. During the core study, FTY720 significantly reduced gadolinium-enhanced (Gd(+)) lesions and annualized relapse rate (ARR) compared with placebo, with no differences between doses. During the extension phase, patients who switched from placebo to FTY720 showed clear reductions in ARR and lesion counts compared with the placebo phase; ARR and lesion counts remained low in patients who continued FTY720 treatment. After 24 months, 79 to 91% of patients were free from Gd(+) lesions and up to 77% of patients remained relapse free. FTY720 was well tolerated; no new safety concerns emerged during months 7 to 24 compared with the 6-month core study. CONCLUSIONS: Once-daily oral treatment with FTY720, 1.25 or 5.0 mg, for up to 2 years, was well tolerated and was associated with low relapse rates and lesion activity.

Photoacoustic depth profiling by cross-correlation using a GaAs light emitting diode.

We present a new approach to depth profiling optically opaque multilayered samples. The presence of interfaces in a sample is revealed by cross-correlating a randomly generated optical probe beam from a GaAs light emitting diode and its generated photoacoustic signal. The technique attains a throughput advantage over previous profiling methods since it operates without an external optical modulator. Random intensity modulation of the light source is achieved by direct current modulation of the diode. We show the effectiveness of our technique by establishing the double-layer structure of a magnetic tape.