Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Development of a Cardiovascular Risk Prediction Model for Individuals with Psoriasis and Psoriatic Arthritis

Aim: Psoriasis and psoriatic arthritis (PsA), collectively known as psoriatic disease (PsD), are characterized by excess cardiovascular (CV) morbidity and mortality compared to the general population. The aim of this thesis is to identify novel biomarkers and disease-specific variables that predict CV risk beyond traditional CV risk factors in patients with PsD. Methods: Data from prospective cohorts of patients with psoriasis and PsA were analyzed. The association of serum metabolites and CV events was investigated. The association between cardiac troponin I (cTnI) and N-terminal pro-brain-type natriuretic peptide (NT-proBNP) and carotid atherosclerosis presence and progression was also tested. Variable selection was used to construct multiple CV risk prediction models – these included traditional CV risk factors, cardio-metabolic biomarkers and disease-specific variables. Metrics of risk prediction were used to determine whether the addition of biomarkers and disease-specific variables to each model improved their predictive performance beyond traditional CV risk factors and the Framingham Risk Score (FRS). Results: The analysis revealed several metabolites associated with CV risk. A model with 13 metabolites significantly improved prediction of CV events beyond a model with age and sex alone. A FRS-adjusted model with 11 metabolites did not improve CV risk discrimination. Investigation of cardiac biomarkers demonstrated that cTnI was independently associated with the burden of carotid atherosclerosis. Elevated cTnI and NT-proBNP were associated with a higher risk of developing CV events independent of traditional CV risk factors. Addition of cTnI or NT-proBNP did not improve the performance of the FRS for predicting CV events. Considering disease-specific variables, a CV risk prediction model for patients with PsD was constructed – this model included traditional CV risk factors and it had excellent performance in predicting CV events within a 5-year period. Disease-specific risk factors did not improve predictive performance beyond traditional CV risk factors alone. Conclusions: Serum metabolite and cardiac biomarkers are associated with the development of incident CV events in patients with PsD, but do not improve predictive performance compared to the FRS. Psoriatic disease related risk factors were not superior to traditional CV risk factors, which performed very well in predicting CV events in patients with PsD.Ph.D

Ethics consultation in paediatric and adult emergency departments: an assessment of clinical, ethical, learning and resource needs

ObjectiveWe sought to understand ethics and education needs of emergency nurses and physicians in paediatric and adult emergency departments (EDs) in order to build ethics capacity and provide a foundation for the development of an ethics education programme.MethodsThis was a prospective cross-sectional survey of all staff nurses and physicians in three tertiary care EDs. The survey tool, called Clinical Ethics Needs Assessment Survey, was pilot tested on a similar target audience for question content and clarity.ResultsOf the 123 participants surveyed, 72% and 84% of nurses and physicians fully/somewhat agreed with an overall positive ethical climate, respectively. 69% of participants reported encountering daily or weekly ethical challenges. Participants expressed the greatest need for additional support to address moral distress (16%), conflict management with patients or families (16%) and resource issues (15%). Of the 23 reported occurrences of moral distress, 61% were associated with paediatric mental health cases. When asked how the ethics consultation service could be used in the ED, providing education to teams (42%) was the most desired method.ConclusionsNurses report a greater need for ethics education and resources compared with their physician colleagues. Ethical challenges in paediatric EDs are more prevalent than adult EDs and nurses voice specific moral distress that are different than adult EDs. These results highlight the need for a suitable educational strategy, which can be developed in collaboration with the leadership of each ED and team of hospital ethicists.</jats:sec

Sex-related differences in patient characteristics, and efficacy and safety of advanced therapies in randomised clinical trials in psoriatic arthritis: a systematic literature review and meta-analysis.

BACKGROUND: Sex-related differences in clinical manifestations and disease outcomes exist in psoriatic arthritis, however, there is limited information on sex-related differences in randomised controlled trials of psoriatic arthritis. We aimed to compare patient characteristics and efficacy and safety of advanced therapies (including biological and targeted synthetic therapies) between male and female patients with psoriatic arthritis participating in randomised controlled trials. METHODS: In this systematic review and meta-analysis, we searched Medline, Embase, and Central databases, and conference abstract archives, from their inception to June 10, 2022, for randomised controlled trials that assessed the efficacy of advanced therapies in psoriatic arthritis. Two reviewers extracted information on participants\u27 characteristics and rates of American College of Rheumatology (ACR) 20 and ACR50 response and minimal disease activity (MDA) by sex. Random-effects models were used to calculate pooled effects of ACR20, ACR50, and MDA in male versus female patients by drug class. FINDINGS: We included 54 trials (11 514 [50·9%] of 22 621 participants were female and 11 107 [49·1%] were male). Sex-disaggregated results were reported in a minority of studies (nine [17%] of 54 reported baseline characteristics by sex, 18 [33%] reported efficacy by sex, and two [4%] reported safety endpoints by sex). At baseline, male patients had lower baseline tender joint count (mean difference -3·01 [95% CI -3·83 to -2·18], health assessment questionnaire scores (-0·28 [-0·33 to -0·24]), pain scores (-4·58 [-6·86 to -2·30]), patient global assessment (-3·22 [-5·27 to -1·17]), and physician global assessment (-1·34 [-2·08 to -0·08]) than did female patients. Male patients had higher baseline psoriasis area and severity index scores (mean difference 1·95 [95% CI 0·78 to 3·11]) and C-reactive protein concentrations (2·57 [0·40 to 4·74]) than did female patients. ACR20 response by sex varied across drug classes, with higher rates in males than females with interleukin (IL)-17 inhibitors (odds ratio [OR] 1·70 [95% CI 1·38-2·11]), IL-23 inhibitor (1·46 [1·20-1·78]), IL-12 and IL-23 inhibitor (2·67 [1·39-5·09]), and tumour necrosis factor (TNF) inhibitors (1·55 [1·11-2·18]), but no difference with JAK and TYK2 inhibitors (1·10 [0·87-1·38]). Similarly, ACR50 response rates were higher in male patients versus female patients in all drug classes, with exception of JAK and TYK2 inhibitors (TNF inhibitors, OR 2·17 [95% CI 1·62-2·90]; IL-17 inhibitors, 1·93 [1·56-2·38]; IL-23 inhibitor, 1·71 [1·25-2·34]; IL-12 and 23 inhibitor, 2·43 [1·14-5·20]; and JAK and TYK2 inhibitors, 1·09 [0·73-1·62]). Male patients were more likely to reach MDA with most drug classes, including IL-17 inhibitors (OR 1·99 [95% CI 1·50-2·63]), IL-23 inhibitors (1·79 [1·29-2·50]), TNF inhibitors (2·62 [1·54-4·44]), and JAK and TYK2 inhibitors (1·77 [1·15-2·73]). Risk of bias was low for most studies. INTERPRETATION: Biological sex of patients with psoriatic arthritis influences their response to advanced therapies, but the effect varies by drug class. Selective reporting might have influenced these results. Future trials should report baseline characteristics and endpoint results by sex. FUNDING: Canadian Rheumatology Association

Predictive Utility of Cardiovascular Risk Prediction Algorithms in Inflammatory Rheumatic Diseases: A Systematic Review

Objective.We performed a systematic review of the literature to describe current knowledge of cardiovascular (CV) risk prediction algorithms in rheumatic diseases.Methods.A systematic search of MEDLINE, EMBASE, and Cochrane Central databases was performed. The search was restricted to original publications in English, had to include clinical CV events as study outcomes, assess the predictive properties of at least 1 CV risk prediction algorithm, and include patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), psoriatic arthritis (PsA), or psoriasis. By design, only cohort studies that followed participants for CV events were selected.Results.Eleven of 146 identified manuscripts were included. Studies evaluated the predictive performance of the Framingham Risk Score, QRISK2, Systematic Coronary Risk Evaluation (SCORE), Reynolds Risk Score, American College of Cardiology/American Heart Association Pooled Cohort Equations (PCE), Expanded Cardiovascular Risk Prediction Score for Rheumatoid Arthritis (ERS-RA), and the Italian Progetto CUORE score. Approaches to improve predictive performance of general risk algorithms in patients with RA included the use of multipliers, biomarkers, disease-specific variables, or a combination of these to modify or develop an algorithm. In both SLE and PsA patients, multipliers were applied to general risk algorithms. In studies of RA and SLE patients, efforts to include nontraditional risk factors, disease-related variables, multipliers, and biomarkers largely failed to substantially improve risk estimates.Conclusion.Our study confirmed that general risk algorithms mostly underestimate and at times overestimate CV risk in rheumatic patients. We did not find studies that evaluated models for psoriasis or AS, which further demonstrates a need for research in these populations.</jats:sec