Derivation and Internal Validation of a Disease-Specific Cardiovascular Risk Prediction Model for Patients With Psoriatic Arthritis and Psoriasis.

OBJECTIVE: To address suboptimal cardiovascular risk prediction in patients with psoriatic disease (PsD), we developed and internally validated a five-year disease-specific cardiovascular risk prediction model. METHODS: We analyzed data from a prospective cohort of participants with PsD without a history of cardiovascular events. Traditional cardiovascular risk factors and PsD-related measures of disease activity were considered as potential predictors. The study outcome included nonfatal and fatal cardiovascular events. A base prediction model included 10 traditional cardiovascular risk factors. Eight PsD-related factors were assessed by adding them to the base model to create expanded models, which were controlled for PsD therapies. Variable selection was performed using Least Absolute Shrinkage and Selection Operator (LASSO) penalized regression with 10-fold cross-validation. Model performance was assessed using measures of discrimination and calibration and measures of sensitivity and specificity. RESULTS: Between 1992 and 2020, 85 of 1,336 participants developed cardiovascular events. Discrimination of the base model (with traditional cardiovascular risk factors alone) was excellent, with an area under the receiver operator characteristic curve (AUC) of 85.5 (95% confidence interval [CI] 81.9-89.1). Optimal models did not select any of the tested disease-specific factors. In a sensitivity analysis, which excluded lipid lowering and antihypertensive treatments, the number of damaged joints was selected in the expanded model. However, this model did not improve risk discrimination compared to the base model (AUC 85.5, 95% CI 82.0-89.1). CONCLUSION: Traditional cardiovascular risk factors alone are effective in predicting cardiovascular risk in patients with PsD. A risk score based on these factors performed well, indicating excellent discrimination and calibration.

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' 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.

2021 GRAPPA Trainee Symposium: A Summary of Oral and Poster Presentations.

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) held a trainee symposium at its 2021 virtual meeting. Dermatology and rheumatology trainees presented their work on psoriasis and psoriatic arthritis (PsA). This report briefly reviews 5 oral presentations: prediction of cardiovascular events in psoriatic disease (PsD), correlation between spine abnormalities and clinical findings, biomechanical stress as a trigger for PsA, differences in DNA methylation among twins with PsD, and critical proteins associated with induction of PsD. In addition, we highlight 22 posters broadly discussing clinical and molecular implications of PsD.

Association of Cardiac Biomarkers With Cardiovascular Outcomes in Patients With Psoriatic Arthritis and Psoriasis: A Longitudinal Cohort Study.

OBJECTIVE: In patients with psoriatic disease (PsD), we determined whether cardiac troponin I (cTnI) and N-terminal pro-brain natriuretic peptide (NT-proBNP) were associated with carotid plaque burden and the development of cardiovascular events independent of the Framingham Risk Score (FRS). METHODS: Among 1,000 patients with PsD, carotid total plaque area (TPA) was measured in 358 participants at baseline. Cardiac troponin I and NT-proBNP were measured using automated clinical assays. The association between cardiac biomarkers and carotid atherosclerosis was assessed by multivariable regression after adjusting for cardiovascular risk factors. Improvement in the prediction of cardiovascular events beyond the FRS was tested using measures of risk discrimination and reclassification. RESULTS: In univariate analyses, cTnI (ß coefficient 0.52 [95% confidence interval (95% CI) 0.3, 0.74], P < 0.001) and NT-proBNP (ß coefficient 0.24 [95% CI 0.1, 0.39], P < 0.001) were associated with TPA. After adjusting for cardiovascular risk factors, the association remained statistically significant for cTnI (adjusted ß coefficient 0.21 [95% CI 0, 0.41], P = 0.047) but not for NT-proBNP (P = 0.21). Among the 1,000 patients with PsD assessed for cardiovascular risk prediction, 64 patients had incident cardiovascular events. When comparing a base model (with the FRS alone) to expanded models (with the FRS plus cardiac biomarkers), there was no improvement in predictive performance. CONCLUSION: In patients with PsD, cTnI may reflect the burden of atherosclerosis, independent of traditional cardiovascular risk factors. Cardiac troponin I and NT-proBNP are associated with incident cardiovascular events independent of the FRS, but further study of their role in cardiovascular risk stratification is warranted.

Incidence of and Risk Factors for Heart Failure in Patients With Psoriatic Disease: A Cohort Study.

OBJECTIVE: To assess the incidence and risk factors for heart failure in patients with psoriatic disease and to describe their electrocardiographic and echocardiographic findings. METHODS: A cohort analysis was conducted involving patients with psoriatic disease followed prospectively from 1978 to 2018. Participants were assessed according to a standard protocol every 6 to 12 months. The primary outcome was the time to first event of heart failure, further classified into ischemic and nonischemic heart failure (secondary outcomes). The association between cardiovascular risk factors, measures of disease activity, and heart failure events was assessed using Cox proportional hazards regression. Electrocardiographic and echocardiographic findings associated with heart failure events were described. RESULTS: A total of 1,994 patients with psoriatic disease were analyzed, with 64 incident heart failure events (38 ischemic, 26 nonischemic). The incidence rate of first heart failure event was 2.85 per 1,000 patient-years. In all events, the most common electrocardiographic findings were atrial fibrillation (22%) and bundle branch blocks (29%). Echocardiogram revealed 37% reduced ejection fraction and 63% preserved ejection fraction. In multivariable analysis, independent risk factors for all heart failure events were ischemic heart disease, adjusted mean tender joint count, adjusted mean swollen joint count, adjusted mean erythrocyte sedimentation rate, adjusted mean C-reactive protein level, and physical function (by Health Assessment Questionnaire) (all P < 0.05). Minimal disease activity state was protective for all heart failure (P < 0.05). CONCLUSION: Increased risk of heart failure is associated with a combination of known cardiovascular risk factors and measures of disease activity, particularly in nonischemic heart failure. The effect of inflammation on heart failure may be partially independent of atherosclerotic disease.

Targeted metabolomic profiling and prediction of cardiovascular events: a prospective study of patients with psoriatic arthritis and psoriasis.

OBJECTIVE: In patients with psoriatic disease (PsD), we sought serum metabolites associated with cardiovascular (CV) events and investigated whether they could improve CV risk prediction beyond traditional risk factors and the Framingham Risk Score (FRS). METHODS: Nuclear magnetic resonance metabolomics identified biomarkers for incident CV events in patients with PsD. The association of each metabolite with incident CV events was analysed using Cox proportional hazards regression models first adjusted for age and sex, and subsequently for traditional CV risk factors. Variable selection was performed using penalisation with boosting after adjusting for age and sex, and the FRS. RESULTS: Among 977 patients with PsD, 70 patients had incident CV events. In Cox regression models adjusted for CV risk factors, alanine, tyrosine, degree of unsaturation of fatty acids and high-density lipoprotein particles were associated with decreased CV risk. Glycoprotein acetyls, apolipoprotein B and cholesterol remnants were associated with increased CV risk. The age-adjusted and sex-adjusted expanded model with 13 metabolites significantly improved prediction of CV events beyond the model with age and sex alone, with an area under the receiver operator characteristic curve (AUC) of 79.9 versus 72.6, respectively (p=0.02). Compared with the FRS alone (AUC=73.9), the FRS-adjusted expanded model with 11 metabolites (AUC=75.0, p=0.72) did not improve CV risk discrimination. CONCLUSIONS: We identify novel metabolites associated with the development of CV events in patients with PsD. Further study of their underlying causal role may clarify important pathways leading to CV events in this population.

The incidence and risk factors for venous thromboembolic events in patients with psoriasis and psoriatic arthritis.

OBJECTIVES: The risk of arterial vascular events is increased in patients with psoriatic disease (PsD), however, limited information exists about the risk of venous thromboembolism (VTE) in these patients. We assessed the incidence and risk factors for VTE in patients with PsD. METHODS: A multicentre cohort study was conducted involving patients with PsD followed prospectively from 1994 to 2020. Information about VTE, including pulmonary embolism (PE) and deep venous thrombosis (DVT), was obtained from provincial hospitalization databases. The incidence rate and cumulative probability of developing VTE were computed. Cox proportional hazards models were used to assess the association between risk factors, including comorbidities and disease-related factors, and the first VTE. RESULTS: A total 2,433 patients with PsD were analysed with 26 incident VTE (7 DVT alone, 12 PE alone, and 7 both PE and DVT). The incidence rates of the first VTE, DVT, and PE were 12, 6.5, and 8.8 events per 10,000 patient-years, respectively. The cumulative proportion of individuals developing VTE was 4.6% by 80 years of age. Independent predictors for VTE included older age, diabetes mellitus, and corticosteroid usage (all p<0.05). CONCLUSION: Older patients with PsD, those with diabetes, and those using corticosteroids are at a higher risk of developing VTE. Risk stratification of patients with these identified risk factors for VTE will allow for more individualized patient management and improved medication selection.

Home Management Versus Primary Care Physician Follow-up of Patients With Distal Radius Buckle Fractures: A Randomized Controlled Trial.

STUDY OBJECTIVE: In patients with a distal radius buckle fracture, we determine whether home removal of a splint and physician follow-up as needed (home management) is noninferior to primary care physician follow-up in 1 to 2 weeks with respect to functional recovery. We also compare groups with respect to health care and patient-level costs. METHODS: This was a noninferiority randomized controlled trial conducted at a tertiary care children's hospital. Eligible patients were randomized to home management versus primary care physician follow-up and received telephone contact at 3 and 6 weeks after the index ED visit. Functional recovery was measured with the Activities Scale for Kids-performance, and participants reported wrist-injury-related health care interventions and expenses. The primary outcome was a comparison of the performance score between groups at 3 weeks. RESULTS: We enrolled 149 patients with mean age 9.5 years (SD 2.7 years), and 81 (54.4%) were male patients. Of the 133 patients (89.3%) with completed 3-week follow-up, the mean Activities Scale for Kids-performance score was 95.4% in the home management group (n=66) and 95.9% in the primary care physician follow-up group (n=67) (mean difference -0.4%; lower bound of the 95% confidence interval -2.4%). There was a mean costs savings of -$100.10 (95% confidence interval -$130.0 to -$70.20) in health care and -$28.2 (95% confidence interval -$49.6 to -$7.0) in patient costs in the home management versus primary care physician follow-up group. CONCLUSION: In patients with distal radius buckle fractures, home management is at least as good as primary care physician follow-up with respect to functional recovery. Implementation of the home management strategy also demonstrated significant cost savings.

Trends in mortality and cause-specific mortality among patients with psoriasis and psoriatic arthritis in Ontario, Canada.

BACKGROUND: There is limited information about mortality rates among patients with psoriasis and psoriatic arthritis (PsA) in North America and their change over the past 2 decades. OBJECTIVE: To compare all-cause and cause-specific mortality rates in patients with psoriasis to the general population in Ontario, Canada, from 1996 to 2016. METHODS: We conducted a population-based, retrospective cohort study of adult residents using administrative health data. All-cause and cause-specific standardized mortality rates, standardized mortality ratios, and excess mortality rates were calculated. RESULTS: 176,858 (2,524 deaths) patients with psoriasis and 15,430 (221 deaths) patients with PsA were identified in 2016. Patients with psoriasis and PsA had standardized excess mortality rates of 1.44 and 2.43 per 1000 population, respectively. Standardized mortality rates decreased by approximately 30% over the study period in both disease groups but remained significantly elevated compared to the general population. The leading causes of death in psoriasis and PsA patients were cancer, circulatory disease, and respiratory conditions. LIMITATIONS: We were unable to classify patients according to disease severity. CONCLUSIONS: Despite improvements in psoriasis treatment, the relative excess mortality, which may be related to risk factors for psoriatic disease, remained unchanged, with an average of approximately 1 to 2 extra deaths per 1,000 patients in 2016.

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.

Adverse Events from Emergency Physician Pediatric Extremity Radiograph Interpretations: A Prospective Cohort Study.

OBJECTIVES: We determined how often emergency physician pediatric musculoskeletal (MSK) radiograph interpretations were discordant to that of a radiologist and led to an adverse event (AE). We also established the variables independently associated with this outcome. METHODS: This prospective cohort study was conducted in an urban, tertiary care children's emergency department (ED). We enrolled children who presented to an ED with an extremity injury and received radiographs. ED physicians documented their radiograph interpretation, which was compared to a radiology reference standard. Patients received telephone follow-up and had institutional medical records reviewed in 3 weeks. An AE occurred if there were clinical sequelae and/or repeat health care visits due to a delay in correct radiograph interpretation. RESULTS: We enrolled 2,302 children (mean [±SD] age = 9.0 [4.4] years; 1,288 (56.0%) male]. Of these, 180 (7.8%; 95% confidence interval = 6.8 to 9.0) ED physician discordant interpretations resulted in an AE. Specifically, there were no negative clinical outcomes; however, relative to cases diagnosed correctly at the index ED, patients whose fracture was not initially identified encountered 77.2% more subsequent ED visits, while those falsely diagnosed with a fracture experienced 41.5% additional orthopedic clinic visits. Odds of an ED discrepant interpretation was significantly higher if a physician's pretest probability of a fracture was ≤ 20% versus> 20% (adjusted odds ratio [aOR] = 1.6), patient's pain score was ≤ 2 versus> 2 (aOR = 1.6), and injury was located in a joint versus other location (aOR = 1.7). CONCLUSIONS: Emergency physician discordant pediatric MSK radiograph interpretations that resulted in an AE occurred with regular frequency in a pediatric ED setting. AEs were primarily an increase in subsequent health care visits. Importantly, a low clinical suspicion for a fracture or injury located in the joint were risk factors for ED physician discordant interpretations.

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

OBJECTIVE: We 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. METHODS: This 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. RESULTS: Of 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. CONCLUSIONS: Nurses 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.

Accuracy of Point-of-Care Ultrasonography for Pediatric Ankle Sprain Injuries.

OBJECTIVES: In children with radiograph fracture-negative lateral ankle injuries, the main objective of this pilot study was to explore the accuracy, sensitivity, and specificity of point-of-care ultrasound (POCUS) performed by a pediatric emergency physician in diagnosing anterior talofibular ligament injuries, radiographically occult distal fibular fractures, and effusions compared with reference standard magnetic resonance imaging (MRI). METHODS: This was a prospective cohort pilot study. Children aged 5 to 17 years with an isolated, acute lateral ankle injury and fracture-negative ankle radiographs were eligible for enrolment. Within 1 week of the injury, enrolled children returned for MRI and POCUS of both ankles. RESULTS: Seven children were enrolled, with a mean age 12.1 (SD, 3.0) years. Overall, POCUS agreed with MRI with respect to anterior talofibular ligament injury in 4 (57%) of 7 cases. Of the 2 cases with MRI-confirmed ligament damage, POCUS accurately identified and graded the extent of ligament damage in 1 case. Point-of-care ultrasound falsely identified ligament injuries in 2 cases. Both imaging modalities confirmed the absence of cortical fractures in all 7 cases. For all findings, POCUS sensitivity and specificity were 57% and 86%, respectively. CONCLUSIONS: In this pilot study, we established that POCUS diagnosed the specific pathology of radiograph-negative lateral ankle injuries with poor sensitivity but good specificity. Thus, POCUS could act as a tool to exclude significant ligamentous and radiographically occult bony injury in these cases. A larger study is needed to validate the utility of POCUS for this common injury.

Parental Knowledge of Trampoline Safety in Children.

OBJECTIVE: Recreational trampoline use is increasing in popularity, with a resulting increase in significant trampoline-related injuries in children. Parents are the best advocates for the safety of their children during recreational trampoline use. Our primary objective was to determine the proportion of parents who were aware of 5 key recommendations for safer recreational trampoline use in children. METHODS: This was a cross-sectional survey of parents whose children presented to a tertiary care pediatric emergency department with an extremity injury. Survey questions were derived and validated using expert opinion, available literature, and pre- and pilot testing of questions on the target audience. RESULTS: Of the 1415 enrolled parents, 654 (46.2%) had regular access to a trampoline and 125 (8.8%) of their children had a history of trampoline injury. A total of 116 (8.2%; 95% confidence interval, 6.8-9.6) parents were aware of all 5 key safety recommendations for home trampoline use. Specifically, the proportion of parents who reported knowledge of the requirement for active supervision, regularly inspected safety equipment, avoiding stunts, multiple jumpers, and use by children 6 years of age and older was 89.0%, 77.2%, 44.3%, 41.6%, and 18.3%, respectively. CONCLUSIONS: Trampoline safety knowledge of the 5 key recommendations among parents was low, specifically with respect to recommended age, number of jumpers, and stunts. Because it is unlikely that use of recreational trampolines will decrease, a harm reduction approach that includes a public knowledge translation strategy of recommendations for safer home use of trampolines is necessary.

Connexin31.1 (Gjb5) deficiency blocks trophoblast stem cell differentiation and delays placental development.

The gap junction channel forming connexins (Cx) Cx31 (Gjb3) and Cx31.1 (Gjb5) are co-expressed in the mouse trophoblast lineage. Inactivation of either gene results in partial embryonic loss at mid gestation (60% and 30%, respectively, between embryonic days E10.5and E13.5) caused by placental phenotypes. Cx31 deficiency results in loss of stem cell potential and enhanced trophoblast giant cell (TGC) differentiation, whereas the molecular role of the co-expressed Cx31.1 remained unclear. It was assumed that both isoforms have overlapping functions and can compete for each loss in placentation as both knockout mice show similar survival rates, reduced placental weights, and growth restricted embryos. Instead, here we show that Cx31.1 has opposed functions in regulating trophoblast differentiation. Cx31.1 deficiency causes a shift in placental subpopulations, reduced area of fetal blood spaces, and a reduced number of secondary TGC in the junctional zone, as shown by stereology at E10.5. Cx31.1 is critical for terminal differentiation of trophoblast cells during placentation resulting in a delayed induction of marker genes Tpbpa, Prl3b1/Pl-2, and Ctsq in Cx31.1-deficient placentas. Derivation and analysis of Cx31.1-deficient trophoblast stem lines clearly indicates a delayed trophoblast differentiation manifested by repression of marker genes for placental subpopulations and continued expression of stem cell marker genes Id2 and Ascl2, which is correlated to enhanced proliferation capacity of differentiating stem cells These findings clarify the disparate actions of Cx31.1 and Cx31 that act in opposition to balance the fate of trophoblast cells during differentiation, with Cx31.1 promoting, and Cx31 delaying terminal differentiation.