Brodalumab for Plaque Psoriasis: A Canadian Real-World Experience at 2-Years Post-Launch.

BACKGROUND: There is limited real-life evidence with brodalumab in patients with plaque psoriasis in Canada. OBJECTIVES: To examine real-world effectiveness of brodalumab in Canadian routine care with a focus on clinician and patient-reported outcomes, as well as measuring continuation rates and persistency. METHODS: Retrospective analysis was conducted on data collected through the brodalumab patient support program (PSP) in Canada for patients initiating brodalumab between June 2018 (PSP launch)- June 2020 with a minimum of 16 weeks follow-up from first dose. Effectiveness was assessed by improvements in PASI, BSA and DLQI; continuation rates and persistency on therapy were reported. RESULTS: Overall, 864 patients (male, 59%; median age, 52 years) were included in the analysis. In a subset of patients with both baseline and follow-up scores, statistically significant improvements were observed: PASI improved from 13.9 to 1.8, BSA improved from 16.6% to 2.5% and DLQI improved from 16.2 to 2.9. Brodalumab demonstrated high continuation rates (89.9%), with similar rates in biologic-naïve and biologic-experienced patients (92.1% and 88.6%, respectively) and in patients who received secukinumab or ixekizumab as their most recent biologic therapy (89.0% and 86.2%, respectively). Persistence at 6, 12, and 18 months was 82.0%, 69.9%, and 63.4%, respectively. CONCLUSIONS: The effectiveness of brodalumab was demonstrated in this Canadian routine care study, with significant improvements in disease severity and patient-reported outcomes. High continuation rates were achieved; including in patients previously treated with IL-17A inhibitors. Future studies will provide further evidence of brodalumab's benefits for the management of plaque psoriasis in the real-world setting.

Unilateral and bilateral repetitive transcranial magnetic stimulation for treatment-resistant depression: a meta-analysis of randomized controlled trials over 2 decades

Background: Approximately 35% of people with depression do not respond to 2 courses of antidepressant medications of adequate dosage, and treatment-resistant depression (TRD) is still a major clinical concern with a great impact on patients, their families, society and the health system. The present meta-analysis evaluates antidepressant efficacy of unilateral and bilateral repetitive transcranial magnetic stimulation (rTMS) in patients with unipolar TRD. Methods: We searched for randomized controlled trials that compared rTMS with sham treatment and were published by Apr. 3, 2017. The primary outcome was improvement in depression scores measured using the Hamilton Rating Scale for Depression. The secondary outcomes were remission and response rates. Two independent review authors screened the studies and extracted the data. Results: Twenty-three studies met the inclusion criteria. Meta-analysis of the depression scores showed a weighted mean difference (WMD) of 3.36 (95% confidence interval [CI] 1.85­4.88) between unilateral rTMS and sham treatment. Stratified data showed that the effect was relatively higher when rTMS was used as an add-on to antidepressant medications (WMD 3.64, 95% CI 1.52­5.76) than when it was used as a stand-alone treatment (WMD 2.47, 95% CI 0.90­4.05). The WMD between bilateral rTMS and sham was 2.67 (95% CI 0.83­4.51), and all studies that contributed to this outcome used rTMS while participants were taking antidepressant medications. The pooled remission and response rates for unilateral rTMS versus sham treatment were 16.0% and 25.1% for rTMS and 5.7% and 11.0% for sham treatment, respectively. The pooled remission and response rates for bilateral rTMS versus sham treatment were 16.6% and 25.4% for rTMS and 2.0% and 6.8% for sham treatment, respectively. Conclusion: This study suggests that rTMS has moderate antidepressant effects and appears to be promising in the short-term treatment of patients with unipolar TRD.

Cytoskeletal remodeling and cellular activation during deformation of neutrophils into narrow channels.

Neutrophils are subjected to mechanical stimulation as they deform into the narrow capillary segments of the pulmonary microcirculation. The present study seeks to understand the changes in the cytoskeletal structure and the extent of biological activation as a result of this process. Neutrophils were passed through narrow polycarbonate filter pores under physiological driving pressures, fixed, and stained downstream to visualize the F-actin content and distribution. Below a threshold capillary size, the cell remodeled its cytoskeleton through initial F-actin depolymerization, followed by recovery and increase in F-actin content associated with formation of pseudopods. This rapid depolymerization and subsequent recovery of F-actin was consistent with our previous observation of an immediate reduction in moduli with eventual recovery when the cells were subjected to deformation. Results also show that neutrophils must be retained in their elongated shape for an extended period of time for pseudopod formation, suggesting that a combination of low driving pressures and small capillary diameters promotes cellular activation. These observations show that mechanical deformation of neutrophils into narrow pulmonary capillaries have the ability to influence cytoskeletal structure, the degree of cellular activation, and migrational tendencies of the cells.

Mechanical deformation of neutrophils into narrow channels induces pseudopod projection and changes in biomechanical properties.

Neutrophils traversing the pulmonary microcirculation are subjected to mechanical stimulation during their deformation into narrow capillaries. To better understand the time-dependant changes caused by this mechanical stimulus, neutrophils were caused to flow into a microchannel, which allowed simultaneous visualization of cell morphology and passive rheological measurement by tracking the Brownian motion of endogenous granules. Above a threshold stimulus, mechanical deformation resulted in neutrophil activation with pseudopod projection. The activation time was inversely correlated to the rate of mechanical deformation experienced by the neutrophils. A reduction in shear moduli was observed within seconds after the onset of the mechanical stimulus, suggesting a sudden disruption of the neutrophil cytoskeleton when subjected to mechanical deformation. However, the magnitude of the reduction in moduli was independent of the degree of deformation. Recovery to nearly the initial values of viscoelastic moduli occurred within 1 min. These observations confirm that mechanical deformation of neutrophils, similar to conditions encountered in the pulmonary capillaries, is not a passive event; rather, it is capable of activating the neutrophils and enhancing their migratory tendencies.