Peripheral Disease Research Articles

Bone Marrow Stromal Cell Mediated Resistance to Mertk Inhibition in Acute Myeloid Leukemia

MERTK is a receptor tyrosine kinase of the TAM family (TYRO-3, AXL, MERTK) that is aberrantly expressed in 80-100% of pediatric and adult primary acute myeloid leukemia (AML) samples. MERTK inhibition mediated by small molecule tyrosine kinase inhibitors (TKIs), UNC2025 or MRX-2843, altered cell cycle progression and induced apoptosis in leukemia cell cultures. Moreover, treatment with these MERTK TKIs prolonged survival in mouse xenograft models of acute leukemia, but was not curative. In these models, treatment with the TKI effectively reduced peripheral disease burden but was less effective in the bone marrow, suggesting a role for the bone marrow microenvironment in therapeutic resistance.To evaluate the role of the bone marrow stromal niche in mediating resistance to MERTK inhibition by MRX-2843, AML cell lines were cultured in the presence of a fibroblast-like cell line (HS27) and induction of cell death and apoptosis was determined by flow cytometry after treatment with MRX-2843 or vehicle. Co-culture with the HS27 cell line significantly reduced cell death in Kasumi-1 AML cell cultures in response to treatment with 200nM MRX-2843 compared to leukemia cells alone (31.9% versus 61.2%, p<0.05). Similar results were observed in NOMO-1 and OCI-AML5 AML cell cultures. Additionally, cell cycle profiles were determined by flow cytometry in the presence or absence of stromal cells and MRX-2843. Treatment of Kasumi-1 cell cultures with 200nM MRX-2843 in the absence of stromal cells resulted in a significant accumulation of cells in G2 phase relative to vehicle-treated cultures (8.9% versus 14.8%, p<0.01) and was accompanied by an increase in γH2AX expression detected by immunoblot. In contrast, there was no change in cell cycle progression or γH2AX expression in cultures treated with MRX-2843 when co-cultured with the stromal cell line. NOMO-1 cells also accumulated in G2 phase in response to treatment with MRX-2843 and were protected from changes in cell cycle progression by co-culture with HS27 cells. Additionally, MERTK inhibition resulted in induction of polyploidy in NOMO-1 cell cultures, but this effect was abrogated in the presence of stromal cells. Collectively these results indicate abrogation of cell cycle progression in leukemia cells in response to treatment with MRX-2843 and demonstrate protection from this effect mediated by stromal cell interactions.The MERTK ligand, GAS6, mediates resistance to cytotoxic chemotherapy in leukemia cells and is a poor prognostic marker in AML. To evaluate the role of the MERTK ligands GAS6 and PROS1 in resistance to MERTK inhibition, their expression in stromal cells was determined by immunoblot. GAS6, but not PROS1, was expressed in HS27 cells; however, MRX-2843 retained its ability to inhibit MERTK phosphorylation in stromal cell co-cultures. We hypothesized that upregulation of the other TAM kinases, AXL and/or TYRO3, may mediate resistance as they share common ligands. To test this hypothesis, Kasumi-1 cells were treated with UNC4241, a small molecule pan-TAM inhibitor, in the presence of stromal cells. While co-culture protected Kasumi-1 cells from MRX-2843 induced apoptosis, treatment with UNC4241 induced apoptosis in the presence of stromal cells (32.7% versus 20.4% in vehicle control, p<0.01).To further evaluate the interactions between stromal cells and leukemia cells, Kasumi-1 cells were cultured in HS27-conditioned medium in the presence or absence of MRX-2843. Conditioned medium was not sufficient to provide protection from MRX-2843 induced apoptosis (74.0% vs. 69.8% in unconditioned medium, p>0.05). Similarly, addition of 500nM exogenous GAS6 or PROS1 did not protect leukemia cells from apoptosis in the presence of MRX-2843. Together, these results suggest that direct cell-cell contact between leukemia and stromal cells is necessary to provide protection.Together these data support a model whereby direct cell-cell contact with stromal cells in the bone marrow niche protects leukemia cells from MRX-2843 induced apoptosis and cell cycle alterations and suggest that bone marrow mobilizing agents may be effective to overcome resistance to MERTK inhibitors. DisclosuresWang:Meryx: Equity Ownership; University of North Carolina: Patents & Royalties. Frye:University of North Carolina: Patents & Royalties; Meryx: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Earp:Meryx: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. DeRyckere:Meryx: Equity Ownership. Graham:Meryx: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Is the SMART risk prediction model ready for real-world implementation? A validation study in a routine care setting of approximately 380 000 individuals.

Reliably quantifying event rates in secondary prevention could aid clinical decision-making, including quantifying potential risk reductions of novel, and sometimes expensive, add-on therapies. We aimed to assess whether the SMART risk prediction model performs well in a real-world setting. We conducted a historical open cohort study using UK primary care data from the Clinical Practice Research Datalink (2000-2017) diagnosed with coronary, cerebrovascular, peripheral, and/or aortic atherosclerotic cardiovascular disease (ASCVD). Analyses were undertaken separately for cohorts with established (≥6 months) vs. newly diagnosed ASCVD. The outcome was first post-cohort entry occurrence of myocardial infarction, stroke, or cardiovascular death. Among the cohort with established ASCVD [n = 244 578, 62.1% male, median age 67.3 years, interquartile range (IQR) 59.2-74.0], the calibration and discrimination achieved by the SMART model was not dissimilar to performance at internal validation [Harrell's c-statistic = 0.639, 95% confidence interval (CI) 0.636-0.642, compared with 0.675, 0.642-0.708]. Decision curve analysis indicated that the model outperformed treat all and treat none strategies in the clinically relevant 20-60% predicted risk range. Consistent findings were observed in sensitivity analyses, including complete case analysis (n = 182 482; c = 0.624, 95% CI 0.620-0.627). Among the cohort with newly diagnosed ASCVD (n = 136 445; 61.0% male; median age 66.0 years, IQR 57.7-73.2), model performance was weaker with more exaggerated risk under-prediction and a c-statistic of 0.559, 95% CI 0.556-0.562. The performance of the SMART model in this validation cohort demonstrates its potential utility in routine healthcare settings in guiding both population and individual-level decision-making for secondary prevention patients.

Chest CT performance and features of COVID-19 in the region of Abu Dhabi, UAE: a single institute study.

ObjectiveWe aim to investigate high-resolution CT features of COVID-19 infection in Abu Dhabi, UAE, and to compare the diagnostic performance of CT scan with RT-PCR test.MethodsData of consecutive patients who were suspected to have COVID-19 infection and presented to our hospital were collected from March 2, 2020, until April 12, 2020. All patients underwent RT-PCR test; out of which 53.8% had chest CT scan done. Using RT-PCR as a standard reference, the sensitivity and specificity of the CT scan were calculated. We also analyzed the most common imaging findings in patients with positive RT-PCR results.ResultsThe typical HRCT findings were seen in 50 scans (65.8%) out of total positive ones; 44 (77.2%) with positive RT-PCR results and 6 (31.6%) with negative results. The peripheral disease distribution was seen in 86%, multilobe involvement in 70%, bilateral in 82%, and posterior in 82% of the 50 scans. The ground glass opacities were seen in 50/74 (89.3%) of the positive RT-PCR group. The recognized GGO patterns in these scans were: rounded 50%, linear 38%, and crazy-paving 24%. Using RT-PCR as a standard of reference, chest HRCT scan revealed a sensitivity of 68.8% and specificity of 70%.ConclusionThe commonest HRCT findings in patients with COVID-19 pneumonia were peripheral, posterior, bilateral, multilobe rounded ground-glass opacities. The performance of HRCT scan can vary depending on multiple factors.

Serum Albumin Modifies the Effect of Peripheral Blood Monocytes on Severity of Diabetic Nephropathy in an Adult Population

BackgroundOur aim in this study was to characterize clinical associations between peripheral blood immune populations and diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus. MethodsWe queried hospital records from an outpatient diabetes primary care clinic between 2018 and 2019 for clinical and laboratory data, including complete blood counts with differentials, serum albumin and globulin, glycated hemoglobin (A1C) and urine albumin-to-creatinine ratio. One hundred ninety-eight patients had complete cross-sectional data with temporally proximate complete blood counts and urine albumin-to-creatinine ratios. After univariable correlation assessment, we used a forward multivariable linear regression model to test the hypothesis that higher numbers of circulating innate immune populations would be associated with DKD, while accounting for known demographic, clinical and laboratory risk factors. We defined DKD as an albumin-to-creatinine ratio of >3 mg/mmol or an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2 from the Chronic Kidney Disease Epidemiology Collaboration. ResultsAdjusted analyses demonstrated significant (p<0.01) associations between higher urine albumin-to-creatinine ratio and peripheral circulating monocytes, independent of other established significant risk factors, including blood pressure, A1C, age and sex. We also identified serum albumin as a potentially important modifying factor of albuminuric kidney disease, which interacts with monocytes in more advanced disease. In contrast, the variable most strongly predictive of eGFR was age. ConclusionsCirculating monocytes and serum albumin are significantly associated with albuminuria, but not eGFR in DKD. These results support the potential role of the innate immune system in diabetic microvascular end-organ damage and urinary protein loss, and may be readily translatable clinical markers to incorporate into risk-assessment models for prognostication in diabetes.

Management of polyvascular disease: a cross-sectional monocentric study in eastern Algeria

Introduction. The rates of atherosclerotic disease as well as its multifocal aspects have been increasing significantly. It is important to know these associations to ensure comprehensive management of this category of patients. Aim. To estimate the frequency of the principal peripheral atherosclerotic associations in patients with coronary artery disease referred to cardiology in the University Hospital of Constantine. Methods. Our study is descriptive, cross-sectional, and mono-centric carried out in the unit of cardiovascular investigations of the Regional Military University Hospital of Constantine. The included patients had at least one significant coronary lesion ≥50 in a principal coronary artery. All our patients underwent an ultrasound evaluation (supra-aortic trunk echo-Doppler, Doppler Ultrasound of the aorta and lower limbs). Data were processed using SPSS Statistics V22. Results. The frequency of the association of Peripheral Artery Disease and Coronary Artery Disease was 34.7% representing the most frequent association. A hemodynamic carotid lesion (≥ 50%) and Abdominal Aortic Aneurysm were associated respectively with Coronary Artery Disease in 12% and 4.6% of patients in the current study. The triple association of coronary artery disease, Abdominal Aortic Aneurysm, and hemodynamic carotid disease was observed in 2.67%, whereas the triple association of Peripheral Artery Disease, coronary artery disease, and carotid stenosis≥50% was observed in 6.67%. The frequency of the association of coronary artery disease, Peripheral Artery Disease, and Abdominal Aortic Aneurysm was estimated at 3, 66%. The therapeutic strategy for multi-focal atherosclerotic disease is still discussed, but coronary artery disease dominates the prognosis. Conclusion. Carrying out a comprehensive assessment of patients with coronary artery disease helps significantly in establishing an adapted and pertinent management with an acceptable BenefitCost Ratio. Keywords: coronary artery disease; peripheral atheromatous disease; pan-vascular therapy.

986-P: Evaluation of Cardiovascular Risk and All-Cause Mortality in Type 1 Diabetes: Comparison of Risk Engines in a 10-Year Follow-up

Type 1 diabetes (T1D) has higher risk of death and CVD compared with general population. Effective risk stratification is essential to implement preventive strategies. We compare the performance of Steno Type 1 Risk Engine (ST1RE) and EURODIAB PCS Risk Engine (EURO-RE) in 733 T1D (M 52%; age 39.3±11.1; DD 18.5±11.6; A1c 7.8±1.2%) with no prior CVD over a 11-yr follow-up (IQR: 9.9-13.0). Both models include age, A1c and albuminuria; ST1RE includes 7 more variables (sex, DD, SBP, LDL-C, eGFR, smoking and exercise), EURO-RE only 2 more variables (WHR, HDL-C). By ST1RE, 453 T1D (61.8%) had low- (&amp;lt;10%), 179 (24.4%) moderate- (10-20%) and 101 (13.8%) high-risk (≥20%); for EURO-RE, estimates were 496 (67.7%), 161 (22.0%) and 76 (10.4%). Regression between 10-yr risks was 0.921 (p&amp;lt;0.0001); concordance of risk strata attribution was 82.5% (n = 605); 98 (13.4%); 30 (4.1%) T1D had higher and, respectively, lower risk by ST1RE vs. EURO-RE. C-statistic for all-cause death (n = 46) was 0.810 (95% CI 0.738-0.882) for ST1RE and 0.802 (0.729-0.875) for EURO-RE. Incidence of CVD was available for 697 T1D (95%). C-statistics for all CVD (n = 32) were 0.770 (0.699-0.841) and 0.777 (0.706-0.849) for ST1RE and EURO-RE, respectively; for coronary events (n = 23) 0.739 (0.650-0.828) and 0.765 (0.683-0.847); for coronary revascularization (n = 14) 0.802 (0.707-0.897) and 0.824 (0.742-0.905). With the limitation of low number of events, C-statistics for stroke (n = 8) were 0.764 (0.596-0.931) and 0.805 (0.654-0.955) for ST1RE and EURO-RE; for peripheral disease (n = 5) 0.794 (0.658-0.931) and 0.733 (0.518-0.948); for ESRD (n = 8) 0.719 (0.544-0.893) and 0.723 (0.529-0.917). Cox regression with backward variable processing selects EURO-RE as covariate for CVD and all other vascular events including ESRD, with ST1RE selected as the strongest covariate for all-cause death. Both ST1RE and the less-demanding EURO-RE are validated and widely available tools to identify high risk T1D individuals. Disclosure M. Garofolo: Consultant; Self; Eli Lilly and Company. E. Gualdani: None. D. Lucchesi: None. P. Falcetta: None. P. Francesconi: None. S. Del prato: Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Speaker’s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novartis Pharmaceuticals Corporation, Sanofi. G. Penno: Advisory Panel; Self; Eli Lilly and Company.

MO760HEPARIN-INDUCED LDL PRECIPITATION IN A NON-DIABETIC DIALYSIS PATIENT AS RESCUE THERAPY FOR CRITICAL ISCHEMIC FOOT: A CASE REPORT

Abstract Background and Aims Dialysis per se represents an independent risk factor for peripheral arterial obliterating disease and in particular for critical ischemic limb. Conventional by-pass surgery or endovascular revascularization frequently did not avoid major limb amputation in dialysis patients or are excluded for wild calcificating atherosclerosis. Extracorporeal LDL-apheresis by means of Heparin-induced LDL Precipitation (H.E.L.P.) is proposed in some cases in combination to the traditional clinical approach. Method Here we describe the case of a 83-year old patient who undergoes thrice weekly hemodialysis from 1 year and who is affected by COPD, ischemic cardiopathy, previous stroke and had a Charson score of 6. He was also affected by dry necrosis of the second toe and parcel of the third toe of the right foot. The patient was not affected by diabetes. Lower limb arteriography showed right tibial artery obstruction anterior to the distal and dorsal third and severe stenosis with short sub-obstruction in subarticular area of the left popliteal artery. The plan foot x-ray excluded osteomyelitis. The vascular surgery consultant found the arterial lesions not suitable for revascularization advising monitoring and dressing of lesions. Nonetheless the patient complained of pain and opioid analgesics were administered. Cardioaspirin and atorvastatin were also administered. The patient was considered eligible for (H.E.L.P.) apheresis for the rescue of his limb. The patient underwent 8 sessions of H.E.L.P. apheresis once a week for eight weeks in a non-dialysis day. His vascular access was a permanent cuffed hemodialysis catheter. H.E.L.P. consists firstly in plasma separation, then apolipoprotein B-containing lipoproteins and fibrinogen are precipitated at a pH-value of 5.12 by the addition of a mixed acetate-heparin buffer to plasma. Before returning the plasma to the patient, the excess heparin is adsorbed and the pH normalized by a bicarbonate dialysis. A total of 3 litres of plasma per session was treated. Each session lasted 3 hours and was carried out in the Dialysis ward. Blood samples were obtained directly before and immediately after each H.E.L.P. apheresis for laboratory measurements. Results A C-reactive protein of 4 mg/dL reflected systemic inflammation. At baseline (prior to H.E.L.P. apheresis), fibrinogen was 394 mg/dL, LDL cholesterol was 122 mg/dL, lipoprotein(a) was 50.5 mg/dL. Total cholesterol was fairly normal even before H.E.L.P. apheresis with concentrations of 170 mg/dL. The pre vs post H.E.L.P. values were significantly reduced for all the parameters considered (p&amp;lt;0.0001). The median reduction rate (RR) per session for fibrinogen was 63.8% (range 57.1-75.3%), for lipoprotein(a) 66.1% (range 54.6-76.5), for LDL-cholesterol 50.8% (range 40-59.3%), for total cholesterol 40.7% (range 35.4-43.5%) (Figure 1). C reactive protein RRs was 61.2% (range 56.2-63.2%). Nonetheless, in the period between the H.E.L.P. apheresis a rebound was observed: for fibrinogen it was 64.9% (range 52.5-73.4%), for total cholesterol 29.2% (range -4 – 54.3%), for LDL cholesterol 36.4% (range -20 – 68.8%), for lipoprotein(a) 69.1% (range 44.1-73.9%). After the 8 sessions of H.E.L.P. apheresis, fibrinogen RR was 21%, LDL cholesterol RR was 75.4%, total cholesterol RR was 64%, lipoprotein(a) RR was 17%. After 6 months the patient underwent minor amputation of the second toe of the right foot, the third toe healed completely. The lesions of the foot before and after 1 year after HELP are showed in Figure 2. Conclusion Drastic reductions of fibrinogen, LDL cholesterol and lipoprotein(a), together with an adequate wound care, reduced the risk of major limb amputation in this dialysis patient with critically ischemic foot that was not qualified for revascularization.

Network Pharmacology and Molecular Docking Study on the Potential Mechanism of Yi-Qi-Huo-Xue-Tong-Luo Formula in Treating Diabetic Peripheral Neuropathy.

Objective To investigate the potential mechanism of action of Yi-Qi-Huo-Xue-Tong-Luo formula (YQHXTLF) in the treatment of diabetic peripheral neuropathy (DPN). Methods Network pharmacology and molecular docking techniques were used in this study. Firstly, the active ingredients and the corresponding targets of YQHXTLF were retrieved using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) platform; subsequently, the targets related to DPN were retrieved using GeneCards, Online Mendelian Inheritance in Man (OMIM), Pharmgkb, Therapeutic Target Database (TTD) and Drugbank databases; the common targets of YQHXTLF and DPN were obtained by Venn diagram; afterwards, the “YQHXTLF Pharmacodynamic Component-DPN Target” regulatory network was visualized using Cytoscape 3.6.1 software, and Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed on the potential targets using R 3.6.3 software. Finally, molecular docking of the main chemical components in the PPI network with the core targets was verified by Autodock Vina software. Results A total of 86 active ingredients and 229 targets in YQHXTLF were screened, and 81 active ingredients and 110 targets were identified to be closely related to diabetic peripheral neuropathy disease. PPI network mapping identified TP53, MAPK1, JUN, and STAT3 as possible core targets. KEGG pathway analysis showed that these targets are mostly involved in AGE-RAGE signaling pathway in diabetic complications, TNF signaling pathway, and MAPK signaling pathway. The molecular docking results showed that the main chemical components of YQHXTLF have a stable binding activity to the core pivotal targets. Conclusion YQHXTLF may act on TP53, MAPK1, JUN, and STAT3 to regulate inflammatory response, apoptosis, or proliferation as a molecular mechanism for the treatment of diabetic peripheral neuropathy, reflecting its multitarget and multipathway action, and providing new ideas to further uncover its pharmacological basis and mechanism of action.

Ataxin-2 gene: a powerful modulator of neurological disorders.

Purpose of reviewTo provide an update on the role of Ataxin-2 gene (ATXN2) in health and neurological diseases.Recent findingsThere is a growing complexity emerging on the role of ATXN2 and its variants in association with SCA2 and several other neurological diseases. Polymorphisms and intermediate alleles in ATXN2 establish this gene as a powerful modulator of neurological diseases including lethal neurodegenerative conditions such as motor neuron disease, spinocerebellar ataxia 3 (SCA3), and peripheral nerve disease such as familial amyloidosis polyneuropathy. This role is in fact far wider than the previously described for polymorphism in the prion protein (PRNP) gene. Positive data from antisense oligo therapy in a murine model of SCA2 suggest that similar approaches may be feasible in humans SCA2 patients.SummaryATXN2 is one of the few genes where a single gene causes several diseases and/or modifies several and disparate neurological disorders. Hence, understanding mutagenesis, genetic variants, and biological functions will help managing SCA2, and several human diseases connected with dysfunctional pathways in the brain, innate immunity, autophagy, cellular, lipid, and RNA metabolism.

Consensus disease definitions for the spectrum of neurologic immune related adverse events.

2647 Background: Expanding FDA-approved indications for immune checkpoint inhibitors in patients with cancer has resulted in both therapeutic success and immune related adverse events (irAEs). Neurologic irAEs (irAE-Ns) have an incidence of 1-12% and a high fatality rate relative to other irAEs. Lack of standardized disease definitions and accurate phenotyping leads to syndrome misclassification and impedes evidence-based treatments and research progress. The objectives of this study were to develop consensus guidance for an approach to irAE-Ns including disease definitions and severity grading. Methods: A working group of 4 neurologists drafted irAE-N consensus guidance and definitions, which were reviewed by the Neuro irAE Disease Definition Panel, consisting of neurologists, oncologists, neuro-oncologists and irAE subspecialists. A modified Delphi consensus process was used, with 2 rounds of anonymous ratings by panelists and 2 virtual meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free text comments. The working group aggregated survey responses and incorporated them into revised definitions. Consensus was based on numeric ratings using the RAND/UCLA Appropriateness Method with prespecified definitions. Results: Twenty-seven panelists from 15 academic medical centers voted on a total of 53 rating scales (6 general guidance, 24 central and 18 peripheral nervous system disease definition components, 3 severity criteria and 2 clinical trial adjudication statements); of these, 77% (41/53) received first round consensus. After revisions, all items received second round consensus. Consensus definitions were achieved for 7 core disorders: irMeningitis, irEncephalitis/Encephalomyelitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders and irMyopathy. For each disorder, 6 sub-classifications are described: disease subtype, diagnostic certainty, severity, autoantibody association, exacerbation of pre-existing disease or de novo presentation and present or absent concurrent irAE. Conclusions: These disease definitions standardize irAE-N classification. They are being incorporated into a multi-institutional registry that our group has initiated to study irAEs. Given consensus on their accuracy and usability from a representative panel group, we anticipate that they can be used broadly across clinical and research settings.

POS0953 PERIPHERAL ARTHRITIS AND HIGHER DISEASE ACTIVITY LEAD TO MORE FUNCTIONAL IMPAIRMENT IN AXIAL SPONDYLOARTHRITIS: LONGITUDINAL ANALYSIS FROM ESPAXIA

Background:Preserving functional ability is among the main goals when treating patients with axSpA. Higher disease activity, reduced axial mobility, and increase spinal radiographic damage, and smoking status have shown to be longitudinally associated with functional worsening. The presence of peripheral arthritis has also been associated with worse functional ability during follow-up, though not in a true longitudinal analysis.Objectives:To investigate whether peripheral arthritis together with disease activity independently contribute to functional impairment over time in patients with axSpA and to evaluate if there are contextual factors modifying this relationship.Methods:Patients with axSpA from the ESPAXIA cohort were followed-up annually over 7 years. Physical function was assessed by the self-reported questionnaire BASFI, disease activity by ASDAS and peripheral arthritis was also recorded. The association between BASFI (outcome), peripheral arthritis and ASDAS (main variables of interest) over time was tested in generalized estimating equations (GEE) models. Models were autoregressive, i.e. adjusted for BASFI 1 year earlier, to allow for a truly longitudinal interpretation. Interactions between each of ASDAS and peripheral arthritis with contextual factors were tested.Results:185 patients were included (77 % male, mean age 42 (SD 13), mean disease duration 9.4 (SD 9.6) years. Mean baseline ASDAS was 2.3 (1.4), mean BASFI 3.9 (2.7) and 17% presented peripheral arthritis during the first visit. After a mean of 3.7 (2.4) years of follow-up, ASDAS and peripheral arthritis independently contributed to explaining BASFI changes over time. Contextual factors did not modify either of the relationships. A true longitudinal relation was proved with the autoregressive GEE model, showing that, adjusted for age, gender, spinal mobility and use of NSAIDs, an increase of one ASDAS unit led to a BASFI 0.48 units higher (ß 0.48 [95% CI 0.39-0.57]), and the presence of peripheral arthritis, to a BASFI 0.44 units higher (ß 0.44 [0.08-0.8]) (Table 1). A gradient was found for ASDAS disease activity states: ASDAS low disease activity (vs ASDAS inactive disease) with an increase in BASFI of 0.67 (0.35-0.98) units compared to ASDAS very high disease activity (vs ASDAS inactive disease) with a BASFI increase of 2.30 (1.90-2.72) units. (Figure 1) No interaction was found between peripheral arthritis and disease activity on BASFI, and similarly, no interactions were found between either ASDAS or peripheral arthritis with age, gender, educational level, smoking status, job type or comorbidities on BASFI.Table 1.Factors longitudinally associated with BASFIAssessmentModel with ASDAS continuousß (95% CI)n=179Model with ASDAS categoricalß (95% CI)n=179Previous BASFI (0-10)0.47 (0.41 to 0.52) †0.44 (0.39 to 0.50)†Age (years)0.007 (-0.005 to 0.02)0.008 (-0.004 to 0.02)Male gender (vs female gender)-0.42 (-0.79 to -0.06) †-0.38 (-0.74 to -0.02)†Peripheral arthritis0.44 (0.08 to 0.80) †0.38 (0.03 to 0.74) †ASDAS-CRP0.48 (0.39 to 0.57) †-ASDAS-CRP categoricalModerate vs inactive disease-0.67 (0.35 to 0.98) †High vs inactive disease-1.70 (1.37 to 2.02) †Very high vs inactive disease-2.30 (1.90 to 2.72) †BASMI (0-10)0.32 (0.24 to 0.41) †0.32 (0.23 to 0.40) †NSAIDs (%)0.38 (0.09 to 0.66) †0.37 (0.09 to 0.64) †† Significant at p&lt;0.05.Figure 1.Longitudinal relationship between ASDAS and BASFIConclusion:Peripheral arthritis and higher disease activity independently lead to more functional impairment in axSpA. Contextual factors do not modify these relationships.Disclosure of Interests:Dafne Capelusnik Speakers bureau: BMS, Grant/research support from: Pfizer, Sofia Ramiro Speakers bureau: Lilly, MSD, Novartis, UCB, Consultant of: AbbVie, Lilly, MSD, Novartis, UCB, Sanofi, Grant/research support from: MSD, Emilce Edith Schneeberger Speakers bureau: Abbvie, BMS, Janssen, Eli Lilly, Boehringer Ingelheim, Pfizer, Grant/research support from: Pfizer, Gustavo Citera Speakers bureau: Abbvie, BMS, Janssen, Pfizer, Grant/research support from: Pfizer, BMS, Janssen

OP0047 IDENTIFICATION OF CLINICAL PHENOTYPES IN PATIENTS WITH AXIAL SPONDYLOARTHRITIS, PERIPHERAL SPONDYLOARTHRITIS AND PSORIATIC ARTHRITIS ACCORDING TO PERIPHERAL MUSCULOSKELETAL MANIFESTATIONS: A CLUSTER ANALYSIS IN THE INTERNATIONAL ASAS-PERSPA STUDY

Background:Patients with a diagnosis of Spondyloarthritis (SpA) and Psoriatic Arthritis (PsA) may have predominant axial or peripheral symptoms, and the frequency and distribution of these symptoms may determine the clinical diagnosis by the rheumatologist (“clinical clusters”). Clustering analysis represents an unsupervised exploratory analysis which tries to identify homogeneous groups of cases (“statistical clusters”) without prior information about the membership for any of the cases.Objectives:To identify “statistical clusters” of peripheral involvement according to the specific location of these symptoms in the whole spectrum of SpA and PsA (without prior information about the diagnosis of the patients), and to evaluate whether these “statistical clusters” are in agreement with the “clinical clusters”.Methods:Cross-sectional and multicentre study with 24 participating countries. Consecutive patients considered by their treating rheumatologist as suffering from either PsA, axial SpA (axSpA) or peripheral SpA (pSpA) were enrolled. Four different cluster analyses were conducted: the first one using information about the specific location from all the peripheral musculoskeletal manifestations (i.e., peripheral arthritis, enthesitis and dactylitis), and thereafter a cluster analysis for each peripheral manifestation individually. Multiple correspondence analyses and k-means clustering methods were used. Distribution of peripheral manifestations and clinical characteristics were compared across the different clusters.Results:4465 patients were included in the analysis. Two clusters were found with regard to the location of all the peripheral manifestations (Fig. 1). Cluster 1 showed a low prevalence of peripheral manifestations in comparison with cluster 2; however, when peripheral involvement appeared in cluster 1, this was mostly represented by arthritis of hip, knee and ankle, as well as enthesitis of the heel. Patients from cluster 1 showed a higher prevalence of males (63% vs 44%), HLA-B27 positivity (69% vs 38%) and axial involvement (80% vs 52%), as well as more frequent diagnosis of axSpA (66% vs 21%) and more frequently fulfilling the ASAS axSpA criteria (69% vs. 41%). Patients from cluster 2 showed a higher prevalence of psoriasis (63% vs 25%), a more frequent diagnosis of PsA (61% vs 19%), and they fulfilled more frequently the peripheral ASAS (26% vs 11%) and the CASPAR criteria (57% vs 19%).Figure 1.Distribution of the peripheral involvement across clustersThree clusters were found with regard to the location of the peripheral arthritis. Clusters 2 and 3 showed a high prevalence of peripheral joint disease, although this was located more predominantly in the lower limbs in cluster 2, and in the upper limbs in cluster 3. Cluster 1 showed a higher prevalence of males, HLA-B27 positivity, axial involvement, a lower presence of psoriasis, a more frequent diagnosis of axSpA and fulfilling the ASAS axSpA criteria in comparison with clusters 2 and 3, respectively. Clusters 2 and 3 showed a higher prevalence of enthesitis and dactylitis in comparison with cluster 1, a more frequent diagnosis of PsA and fulfillment of the CASPAR criteria.Information about the location of enthesitis exhibited three groups: cluster 1 showed a very low prevalence of enthesitis, while cluster 2 and 3 showed a high prevalence of enthesitis, with a predominant involvement of axial enthesis in cluster 2 and peripheral enthesitis in cluster 3.Finally, the analysis of dactylitis also exhibited three clusters that showed a very low prevalence of dactylitis, predominantly toes and predominantly fingers involvement, respectively.Conclusion:These results suggest the presence of heterogeneous patterns of peripheral involvement in SpA and PsA patients without clearly defined groups, confirming the clear overlap of these peripheral manifestations across the different underlying diagnoses.Acknowledgements:This study was conducted under the umbrella of ASAS with unrestricted grant of Abbvie, Pfizer, Lilly, Novartis, UCB, Janssen and Merck.Disclosure of Interests:None declared

Racial and ethnic disparities in coronary, vascular, structural, and congenital heart disease.

Cardiovascular disease (CVD) remains the leading cause of death in the United States. However, percutaneous interventional cardiovascular therapies are often underutilized in Blacks, Hispanics, and women and may contribute to excess morbidity and mortality in these vulnerable populations. The Society for Cardiovascular Angiography and Interventions (SCAI) is committed to reducing racial, ethnic, and sex-based treatment disparities in interventional cardiology patients. Accordingly, each of the SCAI Clinical Interest Councils (coronary, peripheral, structural, and congenital heart disease [CHD]) participated in the development of this whitepaper addressing disparities in diagnosis, treatment, and outcomes in underserved populations. The councils were charged with summarizing the available data on prevalence, treatment, and outcomes and elucidating potential reasons for any disparities. Given the huge changes in racial and ethnic composition by age in the United States (Figure1), it was difficult to determine disparities in rates of diagnosis and we expected to find some racial differences in prevalence of disease. For example, since the average age of patients undergoing transcatheter aortic valve replacement (TAVR) is 80 years, one may expect 80% of TAVR patients to be non-Hispanic White. Conversely, only 50% of congenital heart interventions would be expected to be performed in non-Hispanic Whites. Finally, we identified opportunities for SCAI to advance clinical care and equity for our patients, regardless of sex, ethnicity, or race.

OP0223 DEVELOPMENT AND PRELIMINARY VALIDATION OF ULTRASONOGRAPHIC DISEASE ACTIVITY AND DAMAGE SCORES IN PSORIATIC ARTHRITIS PATIENTS: RESULTS FROM THE UPSTREAM (ULTRASOUND IN PSORIATIC ARTHRITIS TREATMENT) STUDY

Background:The UPSTREAM (NCT03330769) is a 24-month multi-center prospective cohort study that primarily aims to evaluate the additional value of musculoskeletal ultrasound (msk-US) over clinical examination in predicting 6-month minimal disease activity in Psoriatic Arthritis (PsA). (1)Objectives:To develop and preliminarily validate an activity msk-US score and a damage msk-US score for PsA using the UPSTREAM database.Methods:Patients classified with PsA according to CASPAR criteria and starting a new course of therapy for clinically active peripheral joint disease were eligible. The information regarding objectives, study design, clinical and US assessment has already been published (1). The msk-US examination was performed in 42 joints, 36 tendons, 12 entheses and 2 bursae defined through a web-based exercise (2). The sonographic elementary lesions were allocated to disease activity [i.e. synovitis (sy), tenosynovitis (ts), peritendinitis (pt), bursitis (bs) all evaluated both in Grey Scale (GS) and Power Doppler (PD) and active enthesitis (en)] and to damage (i.e. joint erosion, bone proliferation, tendon tear, enthesophyte, calcification and irregular enthesis bone profile). Hands and feet X-ray were assessed using the modified Sharp-Van der Heijde (mSVH) score. A principal component (PC) analysis (PCA) was performed for each score and the number of PCs was defined by means of parallel analysis using baseline data. Each PC was normalized (n) taking into account the proportion between the observed value (e.g. sy-GS count) and the maximum expected value (e.g. 42 for sy-GS). Spearman’ correlation was used to investigate the construct and discrimination validity of the new scores.Results:Between February 2017 and May 2020, 312 PsA patients (155 men), with a mean (SD) age of 52.8 13.4, were enrolled from 19 centers; 22 expert sonographers were involved with substantial agreement for US lesions evaluated (k ≥0.7). The median [IQR] disease duration was 1.3 [0.1-6.1] years and the median [IQR] tender joint and swollen joint counts were 6 [3-13] and 2 [1-5], respectively. The weight derived from PCA for each sonographic lesions and the final equation for calculating the scores are reported in Figure 1 (1A activity and 1B damage). The final msk-US activity score [n(ts-GS + ts-PD)*2.87] + [n(bs-GS + bs-PD)*1.76] + [n(pt-GS + pt-PD)*1.43] + [n(active en)*1.00] + [n(sy-GS)*0.83] + [n(sy-PD)*0.45] has the best construct and discrimination validities according to a significant correlation with all clinical variables usually related to clinical activity (Table 1). The msk-US damage score correlated with mSVH score, HAQ and other clinical variables (Table 1).Table 1.VariablesMsk-US activity scoreMsk-US damage scoreSpearman correlationP-valueSpearman correlationP-valueESR0.1960.0020.0750.235CRP0.209&lt;0.0010.0680.254TJC0.338&lt;0.0010.286&lt;0.001SJC0.338&lt;0.0010.0720.221Dactylitis count0.284&lt;0.001-0.0610.306LEI0.1940.0010.214&lt;0.001Physician GA0.150.0120.0160.793Patient GA activity0.1380.018-0.0730.221Patient GA pain0.1990.001-0.0270.648HAQ0.238&lt;0.0010.1460.014BASDAI0.237&lt;0.0010.1750.003PSAID-90.70.0040.1480.013DAPSA0.392&lt;0.0010.228&lt;0.001Sharp van Der Heijde score0.1150.20.2660.003Figure 1.Conclusion:These newly developed and preliminary validated msk-US activity and damage scores could be used in patients with PsA in the context of observational and controlled trials.

The combined impact of ankle\u2013brachial index and transcutaneous oxygen pressure on mortality in patients with type 2 diabetes and foot ulcers

AimsA diabetic foot ulcer (DFU) is associated with increased cardiovascular risk and mortality, independently of ulcer etiology (ischemic, neuro-ischemic or neuropathic). Ankle–brachial index (ABI) is the most commonly used test when diagnosing peripheral macrovascular disease and is a well-known marker for increased cardiovascular risk. Transcutaneous oxygen pressure (TcPO2) is considered to better evaluate microvascular function and has in previous studies shown correlations with both wound healing and survival. The aim of this study was to evaluate the combined impact of a low TcPO2 (<30 mmHg) and a pathological ABI (<0.9 or ≥1.4) on three-year mortality in patients with DFU.MethodsType 2 diabetes patients aged <90 years, with at least one DFU who underwent vascular assessment with ABI and TcPO2 were screened for participation. The primary endpoint was mortality after three years, assessed from the National Death Registry in Sweden.ResultsThe study enrolled 235 participants with a median age of 76 years. Individuals with either an abnormally high or low ABI in combination with a low TcPO2 had the worst survival rates, with three-year mortality of 54%, compared to 42% in those with one abnormal variable (either ABI or TcPO2), and 21% in those with normal ABI and TcPO2.ConclusionsCombining ABI and TcPO2 when risk stratifying DFU patients seems to provide additional predictive information, not only concerning ulcer healing and limb salvage, but also on survival.

Outcomes in patients with chronic leg wounds in Denmark: A nationwide register-based cohort study.

This study aimed to investigate incidence and predictors of wound healing, relapse, major amputation, and/or death among patients with chronic leg wounds who were referred to specialist treatment at hospital for their condition. A nationwide register‐based cohort study design was applied with 5 years of follow‐up. All patients with diagnoses of chronic leg wounds in Denmark between 2007 and 2012 were included (n = 8394). Clinical, social, and demographic individual‐level linked data from several Danish national registries were retrieved. Incidence rate per 1000 person‐years (PY) was calculated. Predictors were investigated using Cox proportional hazards regression analysis. Incidence rates of having a healed wound was 236 per 1000 PY. For relapse, the incidence rate was 75 per 1000 PY, for amputation 16 per 1000 PY, and for death 100 per 1000 PY. Diabetes, peripheral arteria disease, or other comorbidities were associated with decreased chance of wound healing and increased risk of relapse, major amputation, and death. Regional differences in all four outcomes were detected. Basic or vocational education independently predicted risk of amputation and death. This study provides epidemiological data that may help identify patients at particular risk of poor outcomes. It also elucidates social inequality in outcomes.

IgG4-related Disease of the Nervous Systems

IgG4-related disease is a unique fibroinflammatory disorder with organ system involvement, which was first described in Japan. It is characterized by high serum IgG4 levels and infiltration of IgG4-positive plasma cells in several organs. IgG4-related disease can involve the central and peripheral nervous systems, resulting in hypertrophic pachymeningitis, orbital diseases, hypophysitis, and peripheral nerve disease. Sufficient pathological findings are important for diagnosing IgG4-related disease and distinguishing it from mimics. The 2019 American College of Rheumatology/European League Against Rheumatism Classification Criteria and the 2020 Revised Comprehensive Diagnostic Criteria have recently been published. Herein, we describe a current update of the clinicopathological features, approach to diagnosis, and management of IgG4-related neurological diseases.

Progress in aorta and peripheral cardiovascular disease research

Although coronavirus disease 2019 seems to be the leading topic in research number of outstanding studies have been published in the field of aorta and peripheral vascular diseases likely affecting our clinical practice in the near future. This review article highlights key research on vascular diseases published in 2020. Some studies have shed light in the pathophysiology of aortic aneurysm and dissection suggesting a potential role for kinase inhibitors as new therapeutic options. A first proteogenomic study on fibromuscular dysplasia (FMD) revealed a promising novel disease gene and provided proof-of-concept for a protein/lipid-based FMD blood test. The role of NADPH oxidases in vascular physiology, and particularly endothelial cell differentiation, is highlighted with potential for cell therapy development. Imaging of vulnerable plaque has been an intense field of research. Features of plaque vulnerability on magnetic resonance imaging as an under-recognized cause of stroke are discussed. Major clinical trials on lower extremity peripheral artery disease have shown added benefit of dual antithrombotic (aspirin plus rivaroxaban) treatment.

Triple-disease etiology is common for LUTS in octogenarians: a neuro-urological approach.

Older individuals often have multiple etiologies for their lower urinary tract symptoms (LUTS); i.e., both urologic (U) and neurologic (N) etiologies. Few studies have investigated 'triple disease' (typically one U and two N components) in the LUTS of older adults. Herein, we had specialists from both urology and neurology address triple- and quadruple-etiology disease. This was a retrospective study with a 12-month recruiting period. We ascertained LUTS by standard questionnaires and bladder diaries. Urodynamics, sphincter EMG, prostate echography, and a neurologic examination were conducted for each patient as well as neuroimaging and neurophysiology examinations when appropriate. The diagnoses of the etiologies were based on published criteria. We analyzed the cases of 141 older (age > 65years) adults with LUTS referred from both urology (27%) and neurology departments (73%). The final etiologies were U (n = 69, 49%), N (n = 136, 96%), and a combination (U and N) (n = 77, 55%, overlap counted). The majority of U diagnoses were benign prostatic hyperplasia. The majority of N diagnoses were dementia with Lewy bodies, white matter disease (brain); lumbar spondylosis, and diabetes (peripheral disease). We noted triple-disease etiology in 25% (n = 35), increasing with each decade of age (18.2% of sexagenarians, 23.5% of septuagenarians, 39.1% of octogenarians). However, the differences were not significant. Our results demonstrate that triple disease for LUTS is the most common in octogenarians, and clinicians thus need to untangle LUTS etiologies to provide appropriate care and management of older adults.

Anatomy, Pathophysiology, Molecular Mechanisms, and Clinical Management of Erectile Dysfunction in Patients Affected by Coronary Artery Disease: A Review.

Erectile dysfunction (ED) has been defined as the inability to attain or maintain penile erection sufficient for successful sexual intercourse. ED carries a notable influence on life quality, with significant implications for family and social relationships. Because atherosclerosis of penile arteries represents one of the most frequent ED causes, patients presenting with it should always be investigated for potential coexistent coronary or peripheral disease. Up to 75% of ED patients have a stenosis of the iliac-pudendal-penile arteries, supplying the male genital organ’s perfusion. Recently, pathophysiology and molecular basis of male erection have been elucidated, giving the ground to pharmacological and mechanical revascularization treatment of this condition. This review will focus on the normal anatomy and physiology of erection, the pathophysiology of ED, the relation between ED and cardiovascular diseases, and, lastly, on the molecular basis of erectile dysfunction.