Interleukin-1 mediated hyperinflammation in XIAP-deficiency is associated with defective autophagy.

Deficiency of X-linked Inhibitor of Apoptosis Protein (XIAP) is a rare genetic condition that can present with recurrent episodes of hemophagocytic lymphohistiocytosis (HLH), though the exact mechanisms leading to this hyperinflammatory disorder are unclear. Understanding its biology is critical to developing targeted therapies for this potentially fatal disease. Here we report on a novel multi-exonic intragenic duplication leading to XIAP deficiency with recurrent HLH that demonstrated complete response to interleukin (IL)-1b blockade. We further demonstrate using both primary patient cells and genetically modified THP-1 monocyte cell lines that, contrary to what has previously been shown in mouse cells, XIAP-deficient human macrophages do not produce excess IL-1b when stimulated under standard conditions. Instead, NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated hyperproduction of IL-1b is observed only when the XIAP-deficient cells are stimulated under autophagy-promoting conditions and this correlates with defective autophagic flux as measured by decreased accumulation of the early autophagy marker LC3-II. This work therefore highlights IL-1b blockade as a therapeutic option for patients with XIAP deficiency experiencing recurrent HLH and identifies a critical role for XIAP in promoting autophagy as a means of limiting IL-1b-mediated hyperinflammation during periods of cellular stress.

Social determinants of health inequalities in early phase clinical trials in Northern England.

BACKGROUND: Early phase clinical trials in Oncology represent a subspecialised area where UK patient selection is influenced by access to Experimental Cancer Medicine Centres (ECMCs). Equity of access with respect to social determinants of health (SDoH) were explored for two major ECMCs. METHODS: A retrospective cohort study including all referrals to Newcastle and Manchester ECMCs in 2021 was completed. Consent to screening or pre-screening was stratified against SDoH characteristics, including: Index of Multiple Deprivation (IMD) decile, ethnicity and distance to centre. RESULTS: 1243 patients were referred for trials. IMD quintile 1 (most deprived) patients had reduced likelihood of referral compared to expected population models (OR, 0.67; 95% CI: 0.55 to 0.80, p = <0.0001). IMD quintile 5 (least deprived) had increased likelihood of referral (OR, 1.46; 95% CI: 1.17 to 1.82, p = 0.0007). Living beyond median distance from Manchester reduced the likelihood of consenting to trials (OR, 0.72; 95% CI: 0.55 to 0.94, p = 0.015). Ethnicity data represented a White British propensity. CONCLUSIONS: Inequalities in socioeconomic and geographic factors influence referral and enrolment to early phase clinical trials in Northern England. This has implications for equity of access and generalisability of trial results internationally and warrants further study.

Validation of the EQ-5D-Y-5L parent-proxy version among children with juvenile idiopathic arthritis.

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is the most common type of arthritis among children. It can cause joint pain and permanent physical damage, which affects mobility and daily activities. The EQ-5D-Y-3L self-report version has been validated in JIA, but the validity of EQ-5D-Y-5L remains unknown. We examined the psychometric properties of the EQ-5D-Y-5L parent-proxy version among children with JIA. METHODS: We used data from the Understanding Childhood Arthritis Network Canadian-Dutch collaboration study cohort, including patients with new-onset JIA, and those starting or stopping biologics. Clinical data and the parent-proxy version of the childhood health assessment questionnaire (CHAQ) and EQ-5D-Y-5L were collected. We evaluated the ceiling and floor effect; convergent and divergent validity using Spearman's rank correlation; known-group validity using one-way ANOVA (Analysis of Variance) and effect size; and informativity using Shannon's evenness index. RESULTS: 467 patient visits representing 407 patients were analyzed. The EQ-5D-Y-5L had no ceiling/floor effect. The EQ-5D-Y-5L showed good convergent (e.g., EQ-5D-Y-5L pain/discomfort dimension vs. CHAQ pain index (Spearman's r = 0.74, 95% confidence interval (C.I.): 0.69-0.79)), divergent (e.g., EQ-5D-Y-5L pain/discomfort dimension vs. CHAQ eating dimension (Spearman's r = 0.19, 95% C.I.: 0.09-0.29)) and known-group validity (e.g., mean EQ-5D-Y-5L level summary score for patients with inactive versus active disease status, 6.34 vs. 10.52 (p < 0.001, effect size = 1.20 (95% C.I.: 0.95-1.45)). Shannon's evenness index ranged from 0.52 to 0.88, suggesting most dimensions had relatively even distributions. CONCLUSIONS: In this patient sample, EQ-5D-Y-5L parent-proxy version exhibited construct validity and informativity, suggesting the EQ-5D-Y-5L can be used to measure the quality of life of children with JIA.

Juvenile idiopathic arthritis is the most common type of arthritis affecting children. It can cause pain and permanent physical damage to joints and affects mobility and daily activities. While there is no cure yet, new therapies like biologics are effective. However, biologics are expensive and can have side effects. To decide when is the best time to use these biologics, we need to understand their cost and impact on patients. EQ-5D-Y-5L is a common tool to measure how the disease affects a patient's life. It is unclear whether EQ-5D-Y-5L works well for patients with juvenile idiopathic arthritis. In this study, we compared the EQ-5D-Y-5L to another tool that measures how the illness impacts functional ability. We looked to see if the EQ-5D-Y-5L could tell the difference between children who were more or less sick. We also assessed whether the EQ-5D-Y-5L has the ability to describe patients with different severity in health status. This study indicates that the EQ-5D-Y-5L is a good tool to measure the health of patients with juvenile idiopathic arthritis. Findings from this study support the use of the EQ-5D-Y-5L among this patient population in future clinical trials and research studies.

Kawasaki Disease-Associated Cytokine Storm Syndrome.

Kawasaki disease (KD) is a hyperinflammatory syndrome manifesting as an acute systemic vasculitis characterized by fever, nonsuppurative conjunctival injection, rash, oral mucositis, extremity changes, and cervical lymphadenopathy. KD predominantly affects young children and shares clinical features and immunobiology with other hyperinflammation syndromes including systemic juvenile idiopathic arthritis (sJIA) and multisystem inflammatory syndrome in children (MIS-C). Cytokine storm syndrome (CSS) is an acute complication in ~2% of KD patients; however, the incidence is likely underestimated as many clinical and laboratory features of both diseases overlap. CSS should be entertained when a child with KD is unresponsive to IVIG therapy with recalcitrant fever. Early recognition and prompt institution of immunomodulatory treatment can substantially reduce the mortality and morbidity of CSS in KD. Given the known pathogenetic role of IL-1ß in both syndromes, the early use of IL-1 blockers in refractory KD with CSS deserves consideration.

Von Willebrand factor antigen as a marker of disease activity in childhood-onset antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVE: Von Willebrand Factor (VWF) antigen plays a role in vascular inflammation and thrombosis, both important in the pathogenesis of Antineutrophil Cytoplasmic Antibody-associated vasculitis (AAV). Previous work found that VWF correlates with disease activity in childhood-onset primary CNS vasculitis. We sought to determine the relationship between VWF and disease activity over time in children with AAV. METHODS: AAV patients with more than one VWF level measured were included in this retrospective stuy, and the relationship between active vasculitis, VWF and other disease measures were analyzed. Generalized estimating equations (GEE) analysis was used to account for repeated VWF measurements within a patient. Repeated measures correlation was used to determine associations of paired laboratory observations. Diagnostic performance was evaluated using receiver operating curve (ROC) analysis. RESULTS: 732 total VWF measurements were collected in 33 AAV patients. VWF antigen levels were higher during active disease (median = 2.03 IU/ml, IQR = [1.35, 2.55]) compared with inactive disease (median = 1.18 IU/ml, IQR = [0.94, 1.53). VWF antigen was the only variable that was significantly associated with active disease (OR 3.01, p< 0.001, 95CI [2.3, 3.93]). The effect of VWF did not show a substantial difference between the disease subtypes. There was a moderate positive correlation between VWF antigen and disease activity, with an acceptable sensitivity and specificity rates. CONCLUSION: Increased VWF antigen levels correlate with active vasculitis in this paediatric-onset AAV cohort and may be used as an additional biomarker in childhood AAV.

Pharmacological treatment patterns in patients with juvenile idiopathic arthritis in the Netherlands: a real-world data analysis.

OBJECTIVE: To investigate medication prescription patterns among children with JIA, including duration, sequence and reasons for medication discontinuation. METHODS: This study is a single-centre, retrospective analysis of prospective data from the electronic medical records of JIA patients receiving systemic therapy aged 0-18 years between 1 April 2011 and 31 March 2019. Patient characteristics (age, gender, JIA subtype) and medication prescriptions were extracted and analysed using descriptive statistics, Sankey diagrams and Kaplan-Meier survival methods. RESULTS: Over a median of 4.2 years follow-up, the 20 different medicines analysed were prescribed as monotherapy (n = 15) or combination therapy (n = 48 unique combinations) among 236 patients. In non-systemic JIA, synthetic DMARDs were prescribed to almost all patients (99.5%), and always included MTX. In contrast, 43.9% of non-systemic JIA patients received a biologic DMARD (mostly adalimumab or etanercept), ranging from 30.9% for oligoarticular persistent ANA-positive JIA, to 90.9% for polyarticular RF-positive JIA. Among systemic JIA, 91.7% received a biologic DMARD (always including anakinra). When analysing medication prescriptions according to their class, 32.6% involved combination therapy. In 56.8% of patients, subsequent treatment lines were initiated after unsuccessful first-line treatment, resulting in 68 unique sequences. Remission was the most common reason for DMARD discontinuation (44.7%), followed by adverse events (28.9%) and ineffectiveness (22.1%). CONCLUSION: This paper reveals the complexity of pharmacological treatment in JIA, as indicated by: the variety of mono- and combination therapies prescribed, substantial variation in medication prescriptions between subtypes, most patients receiving two or more treatment lines, and the large number of unique treatment sequences.

Quantifying hospital-associated costs, and accompanying travel costs and productivity losses, before and after withdrawing tumour necrosis factor-alfa inhibitors in juvenile idiopathic arthritis.

OBJECTIVE: To quantify differences in hospital-associated costs, and accompanying travel costs and productivity losses, before and after withdrawing TNFi in JIA patients. METHODS: Retrospective analysis of prospectively collected data from electronic medical records of paediatric JIA patients treated with TNFi, which were either immediately discontinued, spaced (increased treatment interval) or tapered (reduced subsequent doses). Costs of hospital-associated resource use (consultations, medication, radiology procedures, laboratory testing, procedures under general anaesthesia, hospitalisation) and associated travel costs and productivity losses were quantified during clinically inactive disease until TNFi withdrawal (pre-withdrawal period) and compared with costs during the first and second year after withdrawal initiation (first and second year post-withdrawal). RESULTS: Fifty-six patients were included of whom 26 immediately discontinued TNFi, 30 spaced and zero tapered. Mean annual costs were €9,165/patient on active treatment (pre-withdrawal) and decreased significantly to €5,063/patient (-44.8%) and €6,569/patient (-28.3%) in the first and second year post-withdrawal, respectively (p< 0.05). Of these total annual costs, travel costs plus productivity losses were €834/patient, €1,180/patient, and €1,320/patient, in the three periods respectively. Medication comprised 80.7%, 61.5% and 72.4% of total annual costs in the pre-withdrawal, first, and second year post-withdrawal period, respectively. CONCLUSION: In the first two years after initiating withdrawal, the total annual costs are decreased compared with the pre-withdrawal period. However, cost reductions were lower in the second year compared with the first year post-withdrawal, primarily due to restarting or intensifying biologics. To support biologic withdraw decisions, future research should assess the full long-term societal cost impacts, and include all biologics.

The impact of aorto-uni-iliac graft configuration on outcomes of endovascular repair for ruptured abdominal aortic aneurysms.

INTRODUCTION: Endovascular aneurysm repair has improved outcomes for ruptured abdominal aortic aneurysms (rAAA) compared with open repair. We examined the impact of aorto-uni-iliac (AUI) vs standard bifurcated endograft configuration on outcomes in rAAA. METHODS: Patients 18 years or older in the Vascular Quality Initiative database who underwent endovascular aneurysm repair for rAAA from January 2011 to April 2020 were included. Patient characteristics were analyzed by graft configuration: AUI or standard bifurcated. Primary and secondary outcomes included 30-day mortality, postoperative major adverse events (myocardial infarction, stroke, heart failure, mesenteric ischemia, lower extremity embolization, dialysis requirement, reoperation, pneumonia, or reintubation), and 1-year mortality. A subset propensity-score matched cohort was also analyzed. RESULTS: We included 2717 patients: 151 had AUI and 2566 had standard bifurcated repair. There was no significant difference between the groups in terms of age, major medical comorbidities, anatomic aortic neck characteristics, or rates of conversion to open repair. Patients who underwent AUI were more commonly female (30% vs 22%, P = .011) and had a history of congestive heart failure (19% vs 12%, P = .013). Perioperatively, patients who underwent AUI had a significantly higher incidence of cardiac arrest (15% vs 7%, P < .001), greater intraoperative blood loss (1.3 L vs 0.6 L, P < .001), longer operative duration (218 minutes vs 138 minutes, P < .0001), higher incidence of major adverse events (46.3% vs 33.3%, P = .001), and prolonged intensive care unit (7 vs 4.7 days, P = .0006) and overall hospital length of stay (11.4 vs 8.1 days, P = .0003). Kaplan-Meier survival analyses demonstrated significant differences in 30-day (31.1% vs 20.2%, log-rank P = .001) and 1-year mortality (41.7% vs 27.7%, log-rank P = .001). The propensity-score matched cohort demonstrated similar results. CONCLUSIONS: The AUI configuration for rAAA appears to be implemented in a sicker cohort of patients and is associated with worse perioperative and 1-year outcomes compared with a bifurcated graft configuration, which was also seen on propensity-matched analysis. Standard bifurcated graft configuration may be the preferred approach in the management of rAAA unless AUI configuration is mandated by patient anatomy or other extenuating circumstances.

Paediatric inflammatory multisystem syndrome in Canada: population-based surveillance and role of SARS-CoV-2 linkage.

BACKGROUND: Paediatric inflammatory multisystem syndrome (PIMS) is a rare condition temporally associated with SARS-CoV-2 infection. Using national surveillance data, we compare presenting features and outcomes among children hospitalized with PIMS by SARS-CoV-2 linkage, and identify risk factors for intensive care (ICU). METHODS: Cases were reported to the Canadian Paediatric Surveillance Program by a network of >2800 pediatricians between March 2020 and May 2021. Patients with positive versus negative SARS-CoV-2 linkages were compared, with positive linkage defined as any positive molecular or serologic test or close contact with confirmed COVID-19. ICU risk factors were identified with multivariable modified Poisson regression. RESULTS: We identified 406 children hospitalized with PIMS, including 49.8% with positive SARS-CoV-2 linkages, 26.1% with negative linkages, and 24.1% with unknown linkages. The median age was 5.4 years (IQR 2.5-9.8), 60% were male, and 83% had no comorbidities. Compared to cases with negative linkages, children with positive linkages experienced more cardiac involvement (58.8% vs. 37.4%; p < 0.001), gastrointestinal symptoms (88.6% vs. 63.2%; p < 0.001), and shock (60.9% vs. 16.0%; p < 0.001). Children aged ≥6 years and those with positive linkages were more likely to require ICU. CONCLUSIONS: Although rare, 30% of PIMS hospitalizations required ICU or respiratory/hemodynamic support, particularly those with positive SARS-CoV-2 linkages. IMPACT: We describe 406 children hospitalized with paediatric inflammatory multisystem syndrome (PIMS) using nationwide surveillance data, the largest study of PIMS in Canada to date. Our surveillance case definition of PIMS did not require a history of SARS-CoV-2 exposure, and we therefore describe associations of SARS-CoV-2 linkages on clinical features and outcomes of children with PIMS. Children with positive SARS-CoV-2 linkages were older, had more gastrointestinal and cardiac involvement, and hyperinflammatory laboratory picture. Although PIMS is rare, one-third required admission to intensive care, with the greatest risk amongst those aged ≥6 years and those with a SARS-CoV-2 linkage.

Prophylactic sac outflow vessel embolization is associated with improved sac regression in patients undergoing endovascular aortic aneurysm repair.

OBJECTIVE: Type II endoleaks (T2Es), often identified after endovascular aneurysm repair (EVAR), have been associated with late endograft failure and secondary rupture. The number and size of the patent aortic aneurysm sac outflow vessels (ie, the inferior mesenteric, lumbar, and accessory renal arteries) have been implicated as known risk factors for persistent T2Es. Given the technical challenges associated with post-EVAR embolization, prophylactic embolization of aortic aneurysm sac outflow vessels has been advocated to prevent T2Es; however, the evidence available at present is limited. We sought to examine the effects of concomitant prophylactic aortic aneurysm sac outflow vessel embolization in patients undergoing EVAR. METHODS: Patients aged ≥18 years included in the Society for Vascular Surgery Vascular Quality Initiative database who had undergone elective EVAR for intact aneurysms between January 2009 and November 2020 were included in the present study. Patients with a history of prior aortic repair and those without available follow-up data were excluded. The patient demographics, operative characteristics, and outcomes were analyzed by group: EVAR alone vs EVAR with prophylactic sac outflow vessel embolization (emboEVAR). The outcomes of interest were the in-hospital postoperative complication rates, incidence of aneurysmal sac regression (≥5 mm) and T2Es, and reintervention rates during follow-up. RESULTS: A total of 15,060 patients were included. Of these patients, 272 had undergone emboEVAR and 14,788 had undergone EVAR alone. No significant differences were found between the two groups in age, comorbidities, or anatomic characteristics, including the mean maximum preoperative aortic diameter (5.5 vs 5.6 cm; P = .48). emboEVAR was associated with significantly longer procedural times (148 vs 124 minutes; P < .0001), prolonged fluoroscopy times (32 vs 23 minutes; P < .0001), increased contrast use (105 vs 91 mL; P < .0001), without a significant reduction in T2Es at case completion (17.7% vs 16.3%; P = .54). The incidence of postoperative complications (3.7% vs 4.6%; P = .56), index hospitalization reintervention rates (0.7% vs 1.3%; P = .59), length of stay (1.8 vs 2 days; P = .75), and 30-day mortality (0% vs 0%; P = 1.00) were similar between the two groups. At mid-term follow-up (14.6 ± 6.2 months), the emboEVAR group had a significantly greater mean reduction in the maximum aortic diameter (0.69 vs 0.54 cm; P = .006), with a greater proportion experiencing sac regression of ≥5 mm (53.5% vs 48.7%). The reintervention rates were similar between the two groups. On multivariable analysis, prophylactic aortic aneurysm sac outflow vessel embolization (odds ratio, 1.34; 95% confidence interval, 1.04-1.74; P = .024) was a significant independent predictor of sac regression. CONCLUSIONS: Prophylactic sac outflow vessel embolization can be performed safely for patients with intact aortic aneurysms undergoing elective EVAR without significant associated perioperative morbidity or mortality. emboEVAR was associated with significant sac regression compared with EVAR alone at mid-term follow-up. Although no decrease was found in the incidence of T2Es, this technique shows promise, and future efforts should focus on identifying a subset of aneurysm and outflow branch characteristics that will benefit from concomitant selective vs complete prophylactic sac outflow vessel embolization.

Prior infrarenal aortic surgery is not associated with increased risk of spinal cord ischemia after thoracic endovascular aortic repair and complex endovascular aortic repair.

OBJECTIVE: Patients with prior infrarenal aortic intervention represent an increasing demographic of patients undergoing thoracic endovascular aortic repair (TEVAR) and/or complex EVAR. Studies have suggested that prior abdominal aortic surgery is a risk factor for spinal cord ischemia (SCI). However, these results were largely based on single-center experiences with limited multi-institutional and national data that had assessed the clinical outcomes for these patients. The objective of the present study was to evaluate the effect of prior infrarenal aortic surgery on the occurrence of SCI. METHODS: The Society for Vascular Surgery Vascular Quality Initiative database was retrospectively reviewed to identify all patients aged ≥18 years who had undergone TEVAR and/or complex EVAR from January 2012 to June 2020. Patients with previous thoracic or suprarenal aortic repair were excluded. The baseline and procedural characteristics and postoperative outcomes were compared between TEVAR and/or complex EVAR with and without previous infrarenal aortic repair. The primary outcome was postoperative SCI. The secondary outcomes included postoperative hospital length of stay, bowel ischemia, renal ischemia, and 30-day mortality. Multivariate regression was used to determine the independent predictors of postoperative SCI. Additional analysis was performed of the patients who had undergone isolated TEVAR. RESULTS: A total of 9506 patients met the inclusion criteria: 8691 (91.4%) had not undergone prior infrarenal aortic repair and 815 (8.6%) had undergone previous infrarenal aortic repair. Patients with previous infrarenal repair were older with an increased prevalence of chronic kidney disease (P = .001) and cardiovascular risk factors, including hypertension, chronic obstructive pulmonary disease, and positive smoking history (P < .001). These patients also presented with a larger maximal aortic diameter (6.06 ± 1.47 cm vs 5.15 ± 1.76 cm; P < .001) and required more stent-grafts (P < .001) with increased intraoperative blood transfusion requirements (P < .001), and longer procedure times (P < .001). Univariate analysis demonstrated no differences in postoperative SCI, postoperative hospital length of stay, bowel ischemia, or renal ischemia between the two groups. The 30-day mortality was significantly higher in patients with prior infrarenal repair (P = .001). On multivariate regression, prior infrarenal aortic repair was not a predictor of postoperative SCI. In contrast, aortic dissection (odds ratio [OR], 1.65; 95% confidence interval [CI], 1.26-2.16; P < .001), number of stent-grafts deployed (OR, 1.45; 95% CI, 1.30-1.62; P < .001), and units of packed red blood cells transfused intraoperatively (OR, 1.33; 95% CI, 1.03-1.73; P = .032) were independent predictors of postoperative SCI. CONCLUSIONS: Although the patients in the TEVAR and/or complex EVAR group with prior infrarenal aortic repair constituted a sicker cohort with higher 30-day mortality, the rate of SCI was comparable to that of the patients without prior repair. Previous infrarenal repair was not associated with the risk of SCI.

Paediatric-to-adult transition experience in vasculitis: report of a model of care and outcomes.

OBJECTIVES: Transitioning from paediatric to adult care can be challenging. Whereas transition models of care have been shared in some rheumatological conditions, reported experience in vasculitis is lacking. METHODS: Retrospective chart review of adolescents aged 16-18 years assessed at the vasculitis transition clinic by paediatric and adult rheumatologists, and then scheduled for follow-up at the Adult Vasculitis Clinic (Toronto, Canada) from January 2013 until May 2020. RESULTS: Twenty-eight patients were seen at the transition clinic and included. Mean age at transition was 17 years and 11 (± SD 2) months, with a mean follow up from diagnosis of 32 (± 24) months. Most patients had ANCA-associated vasculitis (N=19, 39%), followed by Takayasu's arteritis (N=4, 14%); all but one were in remission at the time of transition. Twenty-six (93%) patients showed up for their first booked adult visit (two did not, were called and rebooked), after a mean of 4 (± 2) months after transition clinic. Subsequently, two patients missed 1 appointment, and three missed ≥ 2 appointments; only one (4%) stopped coming, while in remission for >2 years post-transition. Five (18%) patients were identified to have medication non-adherence after transition. With a mean follow up post-transition of 32 (± 25) months, 7 (25%) patients had minor and five (18%) had major relapses, at a mean of 17 (± 9) and 25 (± 15) months post-transition, respectively (compared to 12 (43%) and 9 (32%) prior to transition). At their last visit, all were in remission, 18 (64%) off glucocorticoids, and damage had remained stable. CONCLUSIONS: This model of care of vasculitis transition clinic resulted in favourable outcomes, as reflected by continuity of follow-up, and no increased risk of relapse.

Wide variation in glucocorticoid dosing in paediatric ANCA-associated vasculitis with renal disease: a paediatric vasculitis initiative study.

OBJECTIVES: High-dose glucocorticoids for remission-induction of ANCA-associated vasculitis are recommended and commonly used in adults, but recent studies suggest lower glucocorticoid doses can reduce toxicity without reducing efficacy. No paediatric-specific data exists to inform optimal glucocorticoid dosing in paediatric ANCA-associated vasculitis (pAAV). Our objectives were to describe glucocorticoid use in pAAV-related renal disease, and to explore associations between glucocorticoid dose, baseline patient characteristics and 12-month outcomes. METHODS: Youth <18 years with pAAV, biopsy-confirmed pauci-immune glomerulonephritis and 12-month follow-up data were included from an international paediatric vasculitis registry. Presenting features and 12-month outcomes (eGFR, glucocorticoid-related adverse effects), were compared between patients receiving no, low-moderate (≤90mg/kg) and high (>90mg/kg) cumulative intravenous methylprednisolone (IVMP), and low (<0.5mg/kg/day prednisone equivalent), moderate (0.5-1.5mg/kg/day) and high (>1.5mg/kg/day) starting doses of oral glucocorticoids. RESULTS: Among 131 patients (101 granulomatosis with polyangiitis, 30 microscopic polyangiitis), 27 (21%) received no IVMP, 64 (49%) low-moderate and 29 (22%) high-dose IVMP, while 9 (7%) received low, 75 (57%) moderate and 47 (36%) high initial doses of oral glucocorticoids. Renal failure at diagnosis (p=0.022) and plasmapheresis use (p=0.0001) were associated with high-dose IVMP. Rates of glucocorticoid-related adverse effects ranged from 15-31% across dose levels, and glucocorticoid dosing did not associate with 12-month outcomes. CONCLUSIONS: Glucocorticoid dosing for pAAV-related renal disease was highly variable, and rates of adverse effects were high across all dosing groups. A significant proportion of patients received oral glucocorticoid or IVMP doses that were discordant with current adult guidelines. Higher glucocorticoid doses did not associate with improved outcomes.

High incidence of patients lost to follow-up after venous thromboembolism diagnosis - Identifying an unmet need for targeted transition of care.

OBJECTIVES: Venous thromboembolism, including deep venous thrombosis and pulmonary embolism, is a major source of morbidity, mortality, and healthcare utilization. Given the prevalence of venous thromboembolism and its associated mortality, our study sought to identify factors associated with loss to follow-up in venous thromboembolism patients. METHODS: This is a single-center retrospective study of all consecutive admitted (inpatient) and emergency department patients diagnosed with acute venous thromboembolism via venous duplex examination and/or chest computed tomography from January 2018 to March 2019. Patients with chronic deep venous thrombosis and those diagnosed in the outpatient setting were excluded. Lost to venous thromboembolism-specific follow-up (LTFU) was defined as patients who did not follow up with vascular, cardiology, hematology, oncology, pulmonology, or primary care clinic for venous thromboembolism management at our institution within three months of initial discharge. Patients discharged to hospice or dead within 30 days of initial discharge were excluded from LTFU analysis. Statistical analysis was performed using STATA 16 (College Station, TX: StataCorp LLC) with a p-value of <0.05 set for significance. RESULTS: During the study period, 291 isolated deep venous thrombosis, 25 isolated pulmonary embolism, and 54 pulmonary embolism with associated deep venous thrombosis were identified in 370 patients. Of these patients, 129 (35%) were diagnosed in the emergency department and 241 (65%) in the inpatient setting. At discharge, 289 (78%) were on anticoagulation, 66 (18%) were not, and 15 (4%) were deceased. At the conclusion of the study, 120 patients (38%) had been LTFU, 85% of whom were discharged on anticoagulation. There was no statistically significant difference between those LTFU and those with follow-up with respect to age, gender, diagnosis time of day, venous thromboembolism anatomic location, discharge unit location, or anticoagulation choice at discharge. There was a non-significant trend toward longer inpatient length of stay among patients LTFU (16.2 days vs. 12.3 days, p = 0.07), and a significant increase in the proportion of LTFU patients discharged to a facility rather than home (p = 0.02). On multivariate analysis, we found a 95% increase in the odds of being lost to venous thromboembolism-specific follow-up if discharged to a facility (OR 1.95, CI 1.1-3.6, p = 0.03) as opposed to home. CONCLUSIONS: Our study demonstrates that over one-third of patients diagnosed with venous thromboembolism at our institution are lost to venous thromboembolism-specific follow-up, particularly those discharged to a facility. Our work suggests that significant improvement could be achieved by establishing a pathway for the targeted transition of care to a venous thromboembolism-specific follow-up clinic.

Multi-institutional patterns of clopidogrel response among patients undergoing transcarotid artery revascularization.

OBJECTIVE: Current guidelines recommend dual antiplatelet therapy (DAPT) in patients undergoing carotid artery stenting. The most common DAPT regimen is aspirin and clopidogrel, a P2Y12 receptor antagonist; however, the prevalence of clopidogrel resistance (CR) in patients undergoing percutaneous coronary interventions may exceed 60%. Few studies have investigated the prevalence and impact of CR in patients undergoing extracranial carotid artery stenting, particularly transcarotid artery revascularization (TCAR). METHODS: Consecutive high-risk patients ≥ 18 years who underwent TCAR for high grade (≥70%) and/or symptomatic (≥50%) carotid stenosis with preoperative P2Y12 testing between August 2019 and December 2021 were identified across five institutions. Preoperative platelet reactivity was measured with the VerifyNow P2Y12 Reaction Unit (PRU) Test (Instrumentation Laboratory, Bedford, MA), with CR defined as PRU ≥ 194 and hyper-response as PRU <70. Patients without preoperative P2Y12 testing within 30 days prior to TCAR or those on a non-clopidogrel P2Y12 inhibitor preoperatively were excluded. The primary outcome of interest was prevalence of CR. Secondary outcomes of interest included the incidence of ischemic and hemorrhagic complications. RESULTS: Of 92 patients identified, the majority were male (59%) and Caucasian (75%) with a mean age of 75 years (±8, range 56-92). Preoperatively, 93% of patients were on aspirin, 100% on clopidogrel, and 13% on therapeutic anticoagulation. At presentation, 36% were symptomatic. The mean preoperative P2Y12 was 156 PRU (±76, range 6-349). In total, 30 (33%) patients met criteria for CR (mean PRU 240 ± 37; range 197-349), and 15 (16%) met criteria for hyper-responder (mean PRU 38 ± 20; range 6-68). There was no significant difference by clopidogrel response phenotype in terms of sex (p = 0.246), race (p = 0.384), or symptomatic presentation (p = 0.956). Postoperatively, the cumulative incidence of stroke and MI was 2.1%, with no statistically significant difference in the incidence of in-hospital stroke (PRU 238, p = 0.489) or MI (PRU 168, p = 1) between clopidogrel phenotypes. Three (3.3%) patients, one CR (PRU 240) and two responders (PRU 119 and PRU 189), experienced postoperative access site hematomas that required no subsequent intervention. No other index hospitalization hemorrhagic complications occurred. CONCLUSIONS: Using preoperative P2Y12 testing with a threshold PRU ≥ 194 to define CR, we identified a high prevalence of CR in patients undergoing TCAR similar to that in the pre-existing coronary literature. We found no significant differences in postoperative ischemic or hemorrhagic complications by clopidogrel response phenotype, although complication rates in the overall study cohort were low. CR may be a spectrum from responder to partial responder to complete non-responder, and this may account for the differences in our CR cohort compared to the ROADSTER 2 protocol deviation cohort. Further investigation is warranted to determine if a quantitative assessment of CR is sufficient to identify patients at risk of developing secondary cerebrovascular ischemic events in this patient population.

Thoracic endovascular aortic repair for symptomatic penetrating aortic ulcers and intramural hematomas is associated with poor outcomes.

BACKGROUND: The natural history of penetrating aortic ulcers (PAUs) and intramural hematomas (IMHs) of the aorta has not been well described. Although repair is warranted for rupture, unremitting chest pain, or growth, no threshold has been established for treating those found incidentally. Thoracic endovascular aortic repair (TEVAR) offers an attractive approach for treating these pathologic entities. However, the periprocedural and postoperative outcomes have not been well defined. METHODS: Patients aged ≥18 years identified in the Vascular Quality Initiative database who had undergone TEVAR for PAUs and/or IMHs from January 2011 to February 2020 were included. We identified 1042 patients, of whom 809 had follow-up data available. The patient demographics and comorbidities were analyzed to identify the risk factors for major adverse events (MAEs) and postoperative and late mortality. RESULTS: The cohort was 54.8% female, and 69.9% were former smokers, with a mean age of 71.1 years. Comorbidities were prevalent, with 57.8% classified as having American Society of Anesthesiologists class 4. Of the 1042 patients, 89.8% had hypertension, 28.3% chronic obstructive pulmonary disease, 17.9% coronary artery disease, and 12.2% congestive heart failure. Patients were predominately symptomatic (74%), and 44.5% had undergone nonelective repair. The MAE incidence was 17%. The independent predictors of MAEs were a history of coronary artery disease, nonwhite race, emergent procedural indication, ruptured presentation, and deployment of two or more endografts. In-hospital mortality was 4.3%. Of the index hospitalization mortalities, 73% were treatment related. For the 809 patients with follow-up (mean, 25.1 ± 19 months), the all-cause mortality was 10.6%. The predictors of late mortality during follow-up included age >70 years, ruptured presentation, and a history of chronic obstructive pulmonary disease and end-stage renal disease. A subset analysis comparing symptomatic (74%) vs asymptomatic (26%) patients demonstrated that the former were frequently women (58.2% vs 45.3%; P < .001), with a greater incidence of MAEs (20.6% vs 6.9%; P < .001), including higher in-hospital reintervention rates (5.9% vs 1.5%; P = .002) and mortality (5.6% vs 0.7%; log-rank P = .015), and a prolonged length of stay (6.9 vs 3.7 days; P < .0001), despite similar procedural risks. During follow-up, late mortality was greater in the symptomatic cohort (12.2% vs 6.5%; log-rank P = .025), with all treatment-related mortalities limited to the symptomatic group. CONCLUSIONS: We found significantly greater morbidity and mortality in symptomatic patients undergoing repair compared with asymptomatic patients, despite similar baseline characteristics. Asymptomatic patients treated with TEVAR had no treatment-related mortality during follow-up, with the overall prognosis largely dependent on preexisting comorbidities. These findings, in conjunction with increasing evidence highlighting the risk of disease progression and attendant morbidity associated with these aortic entities, suggest a need for natural history studies and definitive guidelines on the elective repair of IMHs and PAUs.

Endovascular treatment of popliteal artery aneurysms has comparable long-term outcomes to open repair with shorter lengths of stay.

OBJECTIVE: During the past two decades, the treatment of popliteal artery aneurysms (PAAs) has undergone a transformation. Although open surgical repair (OR) has remained the reference standard for treatment, endovascular repair (ER) has become an attractive alternative for select patient populations. The objective of the present study was to compare the outcomes of OR vs ER of PAAs at a single institution. METHODS: We performed a retrospective review of the medical records for all patients who had undergone repair for PAAs from 1998 to 2017. The baseline patient, anatomic, and operative characteristics and outcomes were compared between the OR and ER cohorts. Intervention and treatment were at the discretion of the surgeon. RESULTS: From 1998 to 2017, 64 patients had undergone repair of 73 PAAs at our tertiary care center. Of the 69 patients (73 PAAs), 29 (33 PAAs) had undergone OR and 35 (40 PAAs) had undergone ER. When comparing the two cohorts, no statistically significant differences were found in the demographic characteristics such as age, gender, or number of runoff vessels. Significantly more patients in the ER group (n = 21; 53%) than in the OR group (n = 7; 21%) had had hyperlipidemia (P = .008) and a previous carotid intervention (6% vs 0%; P = .029). Overall, the presence of symptoms was similar between the two groups. However, the OR group had a significantly higher number of patients who had presented with acute ischemia (P = .01). The length of stay was significantly shorter for the ER cohort (mean, 1.8 days; range, 1-11 days) than for the OR group (mean, 5.4 days; range, 2-13 days; P < .0001). No significant difference was found in the primary or secondary patency rates between the two groups. In the ER group, good runoff (two or more vessels) was a positive predictor for primary patency at 1 year (odds ratio, 3.36; 95% confidence interval, 1.0-11.25). However, it was not in the OR group. Postoperative single and/or dual antiplatelet therapy did not affect primary patency in either cohort. CONCLUSIONS: The results of our study have demonstrated that ER of PAAs is a safe and durable option with patency rates comparable to those with OR and a decreased length of stay, with good runoff a positive predictor for primary patency in the ER cohort.

Adjunctive false lumen intervention for chronic aortic dissections is safe but offers unclear benefit.

OBJECTIVE: Adjunctive false lumen embolization (FLE) with thoracic endovascular aortic repair (TEVAR) in patients with chronic aortic dissection is thought to induce FL thrombosis and favorable aortic remodeling. However, these data are derived from small single-institution experiences and the potential benefit of FLE remains unproven. In this study, we examined perioperative and midterm outcomes of patients with aortic dissection undergoing concomitant TEVAR and FLE.* METHODS: : Patients 18 or older who underwent TEVAR for chronic aortic dissection with known FLE status in the Society for Vascular Surgery Vascular Quality Initiative database between January 2010 and February 2020 were included. Ruptured patients and emergent procedures were excluded. Patient characteristics, operative details and outcomes were analyzed by group: TEVAR with or without FLE. Primary outcomes were in-hospital post-operative complications and all-cause mortality. Secondary outcomes included follow-up mean maximum aortic diameter change, rates of false lumen thrombosis, re-intervention rates, and mortality. RESULTS: 884 patients were included: 46 had TEVAR/FLE and 838 had TEVAR alone. There was no significant difference between groups in terms of age, gender, comorbidities, prior aortic interventions, mean maximum pre-operative aortic diameter (5.1cm vs. 5.0cm, P=0.43), presentation symptomatology, or intervention indication. FLE was associated with significantly longer procedural times (178min vs. 146min, P=0.0002), increased contrast use (134mL vs. 113mL, P=0.02), and prolonged fluoroscopy time (34min vs. 21min, P<0.0001). However, FLE was not associated with a significant difference in post-operative complications (17.4% vs. 13.8%, P=0.51), length of stay (6.5 vs. 5.7 days, P=0.18), or in-hospital all-cause mortality (0% vs. 1.3%, P=1). In mid-term follow-up (median 15.5months, IQR 2.2-36.2 months), all-cause mortality trended lower, but was not significant (2.2% vs. 7.8%); and Kaplan-Meier analysis demonstrated no difference in overall survival between groups (P=0.23). By Cox regression analysis, post-operative complications had the strongest independent association with all-cause mortality (HR 2.65, 95% CI 1.56-4.5, P<0.001). In patients with available follow-up imaging and re-intervention status, mean aortic diameter change (n=337, -0.71cm vs. -0.69cm, P=0.64) and re-intervention rates (n=487, 10% vs. 11.4%, P=1) were similar. CONCLUSIONS: Adjunctive FLE, despite increased procedural times, can be performed safely for patients with chronic dissection without significantly higher overall perioperative morbidity or mortality. TEVAR/FLE demonstrates trends for improved survival and increased rates of FL thrombosis in the treated thoracic segment; however, given the lack of evidence to suggest a significant reduction in re-intervention rates or induction of more favorable aortic remodeling compared to TEVAR alone, the overall utility of this technique in practice remains unclear. Further investigation is needed to determine the most appropriate role for FLE in managing chronic aortic dissections.

Clinical and associated inflammatory biomarker features predictive of short-term outcomes in non-systemic juvenile idiopathic arthritis.

OBJECTIVE: To identify early predictors of disease activity at 18 months in JIA using clinical and biomarker profiling. METHODS: Clinical and biomarker data were collected at JIA diagnosis in a prospective longitudinal inception cohort of 82 children with non-systemic JIA, and their ability to predict an active joint count of 0, a physician global assessment of disease activity of ≤1 cm, and inactive disease by Wallace 2004 criteria 18 months later was assessed. Correlation-based feature selection and ReliefF were used to shortlist predictors and random forest models were trained to predict outcomes. RESULTS: From the original 112 features, 13 effectively predicted 18-month outcomes. They included age, number of active/effused joints, wrist, ankle and/or knee involvement, ESR, ANA positivity and plasma levels of five inflammatory biomarkers (IL-10, IL-17, IL-12p70, soluble low-density lipoprotein receptor-related protein 1 and vitamin D), at enrolment. The clinical plus biomarker panel predicted active joint count = 0, physician global assessment ≤ 1, and inactive disease after 18 months with 0.79, 0.80 and 0.83 accuracy and 0.84, 0.83, 0.88 area under the curve, respectively. Using clinical features alone resulted in 0.75, 0.72 and 0.80 accuracy, and area under the curve values of 0.81, 0.78 and 0.83, respectively. CONCLUSION: A panel of five plasma biomarkers combined with clinical features at the time of diagnosis more accurately predicted short-term disease activity in JIA than clinical characteristics alone. If validated in external cohorts, such a panel may guide more rationally conceived, biologically based, personalized treatment strategies in early JIA.

Associations of clinical and inflammatory biomarker clusters with juvenile idiopathic arthritis categories.

OBJECTIVE: To identify discrete clusters comprising clinical features and inflammatory biomarkers in children with JIA and to determine cluster alignment with JIA categories. METHODS: A Canadian prospective inception cohort comprising 150 children with JIA was evaluated at baseline (visit 1) and after six months (visit 2). Data included clinical manifestations and inflammation-related biomarkers. Probabilistic principal component analysis identified sets of composite variables, or principal components, from 191 original variables. To discern new clinical-biomarker clusters (clusters), Gaussian mixture models were fit to the data. Newly-defined clusters and JIA categories were compared. Agreement between the two was assessed using Kruskal-Wallis analyses and contingency plots. RESULTS: Three principal components recovered 35% (three clusters) and 40% (five clusters) of the variance in patient profiles in visits 1 and 2, respectively. None of the clusters aligned precisely with any of the seven JIA categories but rather spanned multiple categories. Results demonstrated that the newly defined clinical-biomarker lustres are more homogeneous than JIA categories. CONCLUSION: Applying unsupervised data mining to clinical and inflammatory biomarker data discerns discrete clusters that intersect multiple JIA categories. Results suggest that certain groups of patients within different JIA categories are more aligned pathobiologically than their separate clinical categorizations suggest. Applying data mining analyses to complex datasets can generate insights into JIA pathogenesis and could contribute to biologically based refinements in JIA classification.