Molecular and Clinical Characteristics of Different Toxicity Rates in Anti-CD19 Chimeric Antigen Receptor T Cells: Real-World Experience.

Commercially available anti-CD19 chimeric antigen receptor T cells (CARΤ cells) have offered long-term survival to a constantly expanding patient population. Given that novel toxicities including cytokine release syndrome (CRS) and neurotoxicity (ICANS) have been observed, we aimed to document the safety and toxicity of this treatment in a real-world study. We enrolled 31 adult patients referred to our center for CAR T therapy. Tisagenlecleucel was infused in 12 patients, axicabtagene ciloleucel in 14, and brexucabtagene autoleucel in 5. Cytokine release syndrome was noted in 26 patients while neurotoxicity was observed in 7. Tocilizumab was administered for CRS in 18 patients, along with short-term, low-dose steroid administration in one patient who developed grade III CRS and, subsequently, grade I ICANS. High-dose steroids, along with anakinra and siltuximab, were administered in only two MCL patients. With a median follow-up time of 13.4 months, nine patients were then in CR. The progression-free (PFS) and overall survival (OS) rates were 41.2% and 88.1% at one year, respectively. MCL diagnosis, which coincides with the administration of brexucabtagene autoleucel, was the only factor to be independently associated with poor OS (p < 0.001); meanwhile, increased LDH independently predicted PFS (p = 0.027).In addition, CRP at day 14 was associated with a poor OS (p = 0.001). Therefore, our real-world experience confirmed that commercial CAR T therapy can be administered with minimal toxicity.

Platelet microvesicles are associated with the severity of coronary artery disease: comparison between peripheral and coronary circulation.

Microvesicles (MVs) have recently emerged as markers of thrombosis. Furthermore, there is an unexplained residual thrombotic risk is observed in patients with acute coronary syndrome (ACS) and/or stable coronary artery disease (CAD), despite treatment. We measured platelet (PMVs) and erythrocyte (ErMVs) in patients with ACS and stable CAD, both in the peripheral and coronary circulation. We studied consecutive eligible patients during a coronary angiography. Blood samples were collected from the stem of the left coronary artery and femoral artery. PMVs were significantly increased in CAD patients compared to controls. ACS patients had also increased PMVs in coronary and peripheral circulation, compared to controls. Furthermore, ACS patients exhibited increased PMVs in coronary compared to peripheral circulation. Lastly, coronary PMVs were associated with the severity of CAD based on the SYNTAX score. No significant differences were observed in the levels of ErMVs among groups. Therefore, PMVs emerge as novel markers of thrombosis in CAD, further augmenting the vicious cycle of inflammation and thrombosis during ACS. Importantly, coronary PMVs may reflect the severity of CAD in this population.

Endothelial Dysfunction in Patients with Rheumatoid Arthritis: the Role of Hypertension.

PURPOSE OF REVIEW: To review the data on the role of endothelial dysfunction and the impact of hypertension as a potent mediator of cardiovascular disease in patients with rheumatoid arthritis (RA). RECENT FINDINGS: RA represents the most common autoimmune rheumatic disorder and is characterized by chronic systemic inflammation predisposing to cardiovascular complications. Cardiovascular mortality is increased among patients with RA and represents the leading cause of death. Although the exact prevalence is debated, hypertension is increased in RA. Hypertension acts synergistically with chronic inflammation and accounts, at least partially, for the increased cardiovascular morbidity in this group of patients. Endothelial dysfunction is considered a primary process in the pathogenesis of hypertension and cardiovascular diseases and contributes significantly to the development and progression of the associated micro- and macrovascular complications. Even though several studies in patients with RA have shown the presence of endothelial dysfunction with traditional methods, novel biochemical and vascular methods for the evaluation of endothelial dysfunction have been scarcely applied. In addition, it remains unclear whether and to which extent endothelial dysfunction in RA is present regardless of concomitant hypertension, even in well-controlled patients. Hypertension, endothelial dysfunction, and chronic systemic inflammation appear as a mutually reinforcing triad aggravating cardiovascular risk in patients with RA. Detection of endothelial dysfunction in patients with RA in the early stages further aiming at the development of novel therapeutic targets might contribute to prevention of cardiovascular complications and remains under investigation.

Transplant-associated thrombotic microangiopathy: opening Pandora's box.

Transplant-associated thrombotic microangiopathy (TA-TMA) is an early complication of hematopoietic cell transplantation (HCT). A high mortality rate is documented in patients who are refractory to calcineurin inhibitor cessation. Estimates of TA-TMA prevalence vary significantly and are higher in allogeneic compared with autologous HCT. Furthermore, our understanding of the pathophysiology that is strongly related to diagnosis and treatment options is limited. Recent evidence has linked TA-TMA with atypical hemolytic uremic syndrome, a disease of excessive activation of the alternative pathway of complement, opening the Pandora's box in treatment options. As conventional treatment management is highly inefficient, detection of complement activation may allow for early recognition of patients who will benefit from complement inhibition. Preliminary clinical results showing successful eculizumab administration in children and adults with TA-TMA need to be carefully evaluated. Therefore, realizing the unmet needs of better understanding TA-TMA in this complex setting, we aimed to summarize current knowledge focusing on (1) critical evaluation of diagnostic criteria, (2) epidemiology and prognosis, (3) recent evidence of complement activation and endothelial damage and (4) treatment options.

Febuxostat hypersensitivity: another cause of DRESS syndrome in chronic kidney disease?

Febuxostat is a xanthine oxidase inhibitor that during the last years has successfully replaced allopurinol treatment in patients with chronic kidney disease (CKD) and hyperuricemia. Several adverse events have been observed during therapy with febuxostat. DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) syndrome induced by febuxostat has been poorly described, mainly in patient with CKD who previously developed allopurinol hypersensitivity syndrome. DRESS syndrome is characterized by manifold cutaneous reactions and systemic disorders with potential devastating consequences. The underlying pathogenetic mechanisms remain unidentified, though immune responses are often complicated. P-i concept can partially explain the phenomenon. The role of renal insufficiency appears to be crucial and further investigation is required. The present article describes the case of a CKD patient that developed febuxostat-related DRESS syndrome.

Increased thrombotic and impaired fibrinolytic response to acute exercise in patients with essential hypertension: the effect of treatment with an angiotensin II receptor blocker.

Essential hypertension (EH) is characterised by increased thrombotic tendency and impaired fibrinolytic activity. However, exercise-induced changes in coagulation and fibrinolysis have not yet been clarified. We aimed at determining thrombotic and fibrinolytic activity during exercise in patients with EH pre and post treatment with an Angiotensin II receptor blocker. Study 1 consisted of 30 untreated hypertensive (UH) and 15 normotensive (NT) individuals. The UH individuals who received treatment were included in study 2 and were followed up after a 3-month treatment period with valsartan. Thrombin-antithrombin (TAT) complexes and human plasminogen activator inhibitor-1 (PAI-1) were measured as markers of coagulation and fibrinolysis, respectively, at baseline, immediately after a treadmill exercise test and 30 min later. In UH, TAT and PAI-1 levels were significantly increased immediately after peak exercise and decreased 30 min later, as compared with baseline levels. At all time points, UH exhibited significantly higher TAT and PAI-1 levels compared with NT. No significant changes of TAT and PAI-1 levels were observed in NT and in patients post treatment. Acute high-intensity exercise results in impaired thrombotic and fibrinolytic response in untreated patients with EH. Angiotensin II receptor blockade with adequate blood pressure control greatly improves exercise-induced changes in coagulation and fibrinolysis in EH.

The impact of frequently encountered cardiovascular risk factors on sexual dysfunction in rheumatic disorders.

Traditional cardiovascular risk factors have been acknowledged as major contributors to sexual dysfunction in the general population. The purpose of this study was to explore their impact on sexual function in rheumatologic patients. A total of 557 consecutive rheumatologic patients, 449 females and 108 males, had their sexual function evaluated with the Female Sexual Functioning Index (FSFI) and the International Index of Erectile Function (IIEF) questionnaire respectively. Personal data regarding presence of cardiovascular risk factors were collected and analysed in association with the FSFI and IIEF scores. Mean age of the participants was 54.1 ± 14.1 years, mean body mass index was 27.5 ± 5.29 and mean systolic and diastolic blood pressure was 130.5 ± 19.82 and 79.5 ± 10.51 mmHg respectively. Hypertension was present in 39% of the participants, diabetes mellitus in 10.2%, dyslipidaemia in 33.6% and history of cardiovascular events in 8.6%, whereas smoking was recorded by 28.4% and alcohol consumption by 7.4%. Sexual dysfunction affected 68.6% of our study population (73.5% of females and 48.1% of males, p < 0.001). Logistic regression analysis revealed that age was the only factor associated with a significantly higher prevalence of sexual dysfunction (p < 0.001 for both genders, p = 0.013 in males and p < 0.001 in females). Increased age was identified as the only independent predictor of sexual dysfunction in our population. Apart from age, traditional cardiovascular risk factors failed to explain the increased prevalence of sexual dysfunction in these patients. Other contributing factors (physical and/or psychological) might account for the increased occurrence of sexual dysfunction in rheumatic disorders.

Hematopoietic cell transplantation and emerging viral infections.

Viral infections remain important causes of morbidity and mortality in hematopoietic cell transplant recipients. More recent developments in preparative regimens and graft manipulations, as well as the control of well-recognized post-transplant infections by the introduction of prophylaxis and preemptive strategies, have influenced the timing and the epidemiology of infections. As new pathogens, such as human metapneumovirus (HMPV), human bocavirus, human coronaviruses HCoV-NL63 and HCoV-HKU1, human herpesviruses HHV-6 and HHV-7, and polyomaviruses, have emerged, it is fundamental to determine the significance of the newly discovered viruses and their role in the transplantation field. This article summarizes recent data on epidemiology and laboratory diagnosis of new pathogens, as well as clinical features and management of the associated infectious complications. J. Med. Virol. 82:528-538, 2010. (c) 2010 Wiley-Liss, Inc.