Risk of major cardiovascular events in patients with psoriasis receiving biologic therapies: a prospective cohort study.

BACKGROUND: The cardiovascular safety profile of biologic therapies used for psoriasis is unclear. OBJECTIVES: To compare the risk of major cardiovascular events (CVEs; acute coronary syndrome, unstable angina, myocardial infarction and stroke) in patients with chronic plaque psoriasis treated with adalimumab, etanercept or ustekinumab in a large prospective cohort. METHODS: Prospective cohort study examining the comparative risk of major CVEs was conducted using the British Association of Dermatologists Biologics and Immunomodulators Register. The main analysis compared adults with chronic plaque psoriasis receiving ustekinumab with tumour necrosis-α inhibitors (TNFi: etanercept and adalimumab), whilst the secondary analyses compared ustekinumab, etanercept or methotrexate against adalimumab. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using overlap weights by propensity score to balance baseline covariates among comparison groups. RESULTS: We included 5468 biologic-naïve patients subsequently exposed (951 ustekinumab; 1313 etanercept; and 3204 adalimumab) in the main analysis. The secondary analyses also included 2189 patients receiving methotrexate. The median (p25-p75) follow-up times for patients using ustekinumab, TNFi, adalimumab, etanercept and methotrexate were as follows: 2.01 (1.16-3.21), 1.93 (1.05-3.34), 1.94 (1.09-3.32), 1.92 (0.93-3.45) and 1.43 (0.84-2.53) years, respectively. Ustekinumab, TNFi, adalimumab, etanercept and methotrexate groups had 7, 29, 23, 6 and 9 patients experiencing major CVEs, respectively. No differences in the risk of major CVEs were observed between biologic therapies [adjusted HR for ustekinumab vs. TNFi: 0.96 (95% CI 0.41-2.22); ustekinumab vs. adalimumab: 0.81 (0.30-2.17); etanercept vs. adalimumab: 0.81 (0.28-2.30)] and methotrexate against adalimumab [1.05 (0.34-3.28)]. CONCLUSIONS: In this large prospective cohort study, we found no significant differences in the risk of major CVEs between three different biologic therapies and methotrexate. Additional studies, with longer term follow-up, are needed to investigate the potential effects of biologic therapies on incidence of major CVEs

Medication safety in community pharmacy: a qualitative study of the sociotechnical context

<p>Abstract</p> <p>Background</p> <p>While much research has been conducted on medication safety, few of these studies have addressed primary care, despite the high volume of prescribing and dispensing of medicines that occurs in this setting. Those studies that have examined primary care dispensing emphasised the need to understand the role of sociotechnical factors (that is, the interactions between people, tasks, equipment and organisational structures) in promoting or preventing medication incidents. The aim of this study was to identify sociotechnical factors that community pharmacy staff encounter in practice, and suggest how these factors might impact on medication safety.</p> <p>Methods</p> <p>Sixty-seven practitioners, working in the North West of England, took part in ten focus groups on risk management in community pharmacy. The data obtained from these groups was subjected to a qualitative analysis to identify recurrent themes pertaining to sociotechnical aspects of medication safety.</p> <p>Results</p> <p>The findings indicated several characteristics of participants' work settings that were potentially related to medication safety. These were broadly classified as relationships involving the pharmacist, demands on the pharmacist and management and governance of pharmacists.</p> <p>Conclusion</p> <p>It is recommended that the issues raised in this study be considered in future work examining medication safety in primary care.</p

Randomized Trial Replication Using Observational Data for Comparative Effectiveness of Secukinumab and Ustekinumab in Psoriasis: A Study From the British Association of Dermatologists Biologics and Immunomodulators Register.

Importance: Treatments for psoriasis may be less effective in everyday practice than in clinical trials. Emulating a target trial using data from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) can provide treatment effect estimates that are robust and can inform both clinicians and regulatory bodies. Objectives: To assess the comparative effectiveness of ustekinumab and secukinumab in patients with psoriasis, and to test whether the relative effectiveness estimate of the CLEAR trial, a randomized clinical trial that compared secukinumab with ustekinumab for psoriasis, can be replicated. Design, Setting, and Participants: This comparative effectiveness research study used a target trial emulation approach and was performed between November 2007 and August 2019. Data were obtained from BADBIR, a multicenter longitudinal pharmacovigilance register of patients with moderate to severe psoriasis in the United Kingdom and Republic of Ireland. Participants had chronic plaque psoriasis, were 18 years or older, and had at least 1 record of a Psoriasis Area and Severity Index (PASI) of 12 or higher before their initiation to secukinumab or ustekinumab. Propensity score (PS) 1:1 matched analysis and inverse probability treatment weighted analysis were performed. Main Outcomes and Measures: The primary outcomes were the risk ratio (RR) and the risk difference (RD) for achieving PASI of 2 or lower after 12 months of therapy for secukinumab compared with ustekinumab. Methods to account for missing outcome data were complete case analysis, nonresponder imputation, last observation carried forward, inverse probability of censoring weighting, and multiple imputation. Regulatory and estimate agreement metrics were used to benchmark the effect estimates in this study against those in the CLEAR trial. Results: A total of 1231 patients were included in the analysis, with 917 receiving ustekinumab and 314 receiving secukinumab. Secukinumab was superior to ustekinumab in all analyses, except under the nonresponder imputation method, in the proportion of participants achieving a PASI of 2 or lower (PS-weighted complete case analysis: RR, 1.28 [95% CI, 1.06-1.55]; RD, 11.9% [1.6-22.1]). All analyses, except for nonresponder imputation, reached regulatory agreement in both PS-matching and PS-weighted analyses. Conclusions and Relevance: This comparative effectiveness study found that secukinumab resulted in more patients achieving a PASI of 2 or lower after 12 months of therapy compared with ustekinumab in patients with psoriasis. Target trial emulation in this study resulted in regulatory and estimate agreement with the CLEAR randomized clinical trial; further such studies may help fill the evidence gap when comparing other systemic therapies for psoriasis

Overexpression of cathepsin K in mice decreases collagen deposition and lung resistance in response to bleomycin-induced pulmonary fibrosis

<p>Abstract</p> <p>Background</p> <p>Lung fibrosis is a devastating pulmonary disorder characterized by alveolar epithelial injury, extracellular matrix deposition and scar tissue formation. Due to its potent collagenolytic activity, cathepsin K, a lysosomal cysteine protease is an interesting target molecule with therapeutic potential to attenuate bleomycin-induced pulmonary fibrosis in mice. We here tested the hypothesis that over-expression of cathepsin K in the lungs of mice is protective in bleomycin-induced pulmonary fibrosis.</p> <p>Methods</p> <p>Wild-type and cathepsin K overexpressing (cathepsin K transgenic; cath K tg) mice were challenged intratracheally with bleomycin and sacrificed at 1, 2, 3 and 4 weeks post-treatment followed by determination of lung fibrosis by estimating lung collagen content, lung histopathology, leukocytic infiltrates and lung function. In addition, changes in cathepsin K protein levels in the lung were determined by immunohistochemistry, real time RT-PCR and western blotting.</p> <p>Results</p> <p>Cathepsin K protein levels were strongly increased in alveolar macrophages and lung parenchymal tissue of mock-treated cathepsin K transgenic (cath K tg) mice relative to wild-type mice and further increased particularly in cath K tg but also wild-type mice in response to bleomycin. Moreover, cath K tg mice responded with a lower collagen deposition in their lungs, which was accompanied by a significantly lower lung resistance (R_L) compared to bleomycin-treated wild-type mice. In addition, cath K tg mice responded with a lower degree of lung fibrosis than wild-type mice, a process that was found to be independent of inflammatory leukocyte mobilization in response to bleomycin challenge.</p> <p>Conclusion</p> <p>Over-expression of cathepsin K reduced lung collagen deposition and improved lung function parameters in the lungs of transgenic mice, thereby providing at least partial protection against bleomycin-induced lung fibrosis.</p

Characterization of the innate immune response to chronic aspiration in a novel rodent model

<p>Abstract</p> <p>Background</p> <p>Although chronic aspiration has been associated with several pulmonary diseases, the inflammatory response has not been characterized. A novel rodent model of chronic aspiration was therefore developed in order to investigate the resulting innate immune response in the lung.</p> <p>Methods</p> <p>Gastric fluid or normal saline was instilled into the left lung of rats (n = 48) weekly for 4, 8, 12, or 16 weeks (n = 6 each group). Thereafter, bronchoalveolar lavage specimens were collected and cellular phenotypes and cytokine concentrations of IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-10, GM-CSF, IFN-gamma, TNF-alpha, and TGF-beta were determined.</p> <p>Results</p> <p>Following the administration of gastric fluid but not normal saline, histologic specimens exhibited prominent evidence of giant cells, fibrosis, lymphocytic bronchiolitis, and obliterative bronchiolitis. Bronchoalveolar lavage specimens from the left (treated) lungs exhibited consistently higher macrophages and T cells with an increased CD4:CD8 T cell ratio after treatment with gastric fluid compared to normal saline. The concentrations of IL-1alpha, IL-1beta, IL-2, TNF-alpha and TGF-beta were increased in bronchoalveolar lavage specimens following gastric fluid aspiration compared to normal saline.</p> <p>Conclusion</p> <p>This represents the first description of the pulmonary inflammatory response that results from chronic aspiration. Repetitive aspiration events can initiate an inflammatory response consisting of macrophages and T cells that is associated with increased TGF-beta, TNF-alpha, IL-1alpha, IL-1beta, IL-2 and fibrosis in the lung. Combined with the observation of gastric fluid-induced lymphocyitic bronchiolitis and obliterative bronchiolitis, these findings further support an association between chronic aspiration and pulmonary diseases, such as obliterative bronchiolitis, pulmonary fibrosis, and asthma.</p

Expanding the clinical spectrum of biglycan-related Meester-Loeys syndrome

\ua9 The Author(s) 2024.Pathogenic loss-of-function variants in BGN, an X-linked gene encoding biglycan, are associated with Meester-Loeys syndrome (MRLS), a thoracic aortic aneurysm/dissection syndrome. Since the initial publication of five probands in 2017, we have considerably expanded our MRLS cohort to a total of 18 probands (16 males and 2 females). Segregation analyses identified 36 additional BGN variant-harboring family members (9 males and 27 females). The identified BGN variants were shown to lead to loss-of-function by cDNA and Western Blot analyses of skin fibroblasts or were strongly predicted to lead to loss-of-function based on the nature of the variant. No (likely) pathogenic missense variants without additional (predicted) splice effects were identified. Interestingly, a male proband with a deletion spanning the coding sequence of BGN and the 5’ untranslated region of the downstream gene (ATP2B3) presented with a more severe skeletal phenotype. This may possibly be explained by expressional activation of the downstream ATPase ATP2B3 (normally repressed in skin fibroblasts) driven by the remnant BGN promotor. This study highlights that aneurysms and dissections in MRLS extend beyond the thoracic aorta, affecting the entire arterial tree, and cardiovascular symptoms may coincide with non-specific connective tissue features. Furthermore, the clinical presentation is more severe and penetrant in males compared to females. Extensive analysis at RNA, cDNA, and/or protein level is recommended to prove a loss-of-function effect before determining the pathogenicity of identified BGN missense and non-canonical splice variants. In conclusion, distinct mechanisms may underlie the wide phenotypic spectrum of MRLS patients carrying loss-of-function variants in BGN