TNF inhibition in vasculitis management in adenosine deaminase 2 deficiency (DADA2).

BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited autoinflammatory disorder caused by a loss of functional ADA2 protein. TNF inhibition (TNFi) has proven to be highly effective in treating inflammatory manifestations. OBJECTIVE: We sought to explore the pathophysiology and the underlying mechanisms of TNF-inhibitor response in these patients. METHODS: We performed Sanger sequencing of the ADA2 gene. We used flow cytometry, intracellular cytokine staining, transcriptome analysis, immunohistochemistry, and cell differentiation experiments to define an inflammatory signature in patients with DADA2 and studied their response to TNF-inhibitor treatment. RESULTS: We demonstrated increased inflammatory signals and overproduction of cytokines mediated by IFN and nuclear factor kappa B pathways in patients' primary cells. Treatment with TNFi led to reduction in inflammation, rescued the skewed differentiation toward the proinflammatory M1 macrophage subset, and restored integrity of endothelial cells in blood vessels. We also report 8 novel disease-associated variants in 7 patients with DADA2. CONCLUSIONS: Our data explore the cellular mechanism underlying effective treatment with TNFi therapies in DADA2. DADA2 vasculitis is strongly related to the presence of activated myeloid cells, and the endothelial cell damage is rescued with anti-TNF treatment.

First-in-human experience of the Bashir Endovascular Catheter in the treatment of iliocaval deep vein thrombosis.

Deep vein thrombosis (DVT) is a common disorder affecting approximately 900,000 new patients in the United States each year. Although the mainstay of treatment of DVT patients is therapeutic anticoagulation, some patients remain significantly symptomatic and therefore require more advanced interventions such as catheter-directed thrombolysis (CDT). We describe a case series of 13 patients with acute symptomatic inferior vena cava (IVC) and iliofemoral DVT that were treated with CDT using the Bashir Endovascular Catheter (BEC). We report the first-in-human use of BEC, which is a novel pharmacomechanical thrombolysis device. All the treated patients had complete and rapid resolution of their symptoms with excellent venous outflow. Despite initial promising results, larger studies using this catheter design will be needed to assess the role of BEC-directed therapy on rates of post-thrombotic syndrome and bleeding complications.

Sex differences in utilization and outcomes of catheter-directed thrombolysis in patients with proximal lower extremity deep venous thrombosis - Insights from the Nationwide Inpatient Sample.

Catheter-directed thrombolysis (CDT) is being increasingly used for the treatment of proximal lower extremity (LE) deep venous thrombosis (DVT). However, sex differences in utilization and safety outcomes of CDT in these patients are unknown. The Nationwide Inpatient Sample (NIS) database was used to identify all patients with a principal discharge diagnosis of proximal LE or caval DVT who underwent CDT between January 2005 and December 2011 in the United States. We evaluated the comparative safety outcomes of CDT among a propensity-matched group of 1731 men versus 1731 women. Among 108,243 patients with proximal LE or caval DVT, 4826 patients (4.5%) underwent CDT. Overall, women underwent CDT less often compared to men (4.1% vs 4.9%, p<0.01, respectively). The rates of CDT increased between 2005 and 2011 for both women (2.1% to 5.9%, p<0.01) and men (2.5% to 7.5%, p<0.01). There was no significant difference in in-hospital mortality (1.2% vs 1.3%, p=0.76). Women were noted to have higher rates of blood transfusions (11.7% vs 8.8%, p<0.01), but lower rates of intracranial hemorrhage (0.5% vs 1.2%, p=0.03) and gastrointestinal bleeding (0.9% vs 2.2%, p<0.01) compared with men. Women were more likely to undergo inferior vena cava filter placement (37.0% vs 32.1%, p<0.01). In this large nationwide cohort, women with proximal DVT were less likely to receive CDT compared to men. Although mortality rates were similar, women were noted to have higher blood transfusion rates while men had more episodes of intracranial and gastrointestinal bleeding.

Increased levels of the inflammatory biomarker C-reactive protein at baseline are associated with childhood sickle cell vasocclusive crises.

Several lines of evidence suggest that sickle cell disease (SCD) is associated with a chronic inflammatory state. In this study of 70 children with SCD at steady state evaluated by a broad panel of biomarkers representing previously examined mechanisms of pathogenicity in SCD, high sensitivity C-reactive protein (hs-CRP), a marker of low-grade, systemic inflammation, emerged as the most significant laboratory correlate of hospitalizations for pain or vaso-occlusive (VOC) events. While markers of increased haemolytic status, endothelial activation and coagulation activation all correlated positively with VOC events by univariate analysis, baseline hs-CRP levels provided the most significant contribution to the association in multiple regression models (22%), and, hs-CRP, along with age, provided the best fit in negative binomial models. These data highlight the clinical relevance of the role of inflammation in paediatric VOC, providing both a rationale for future therapeutic strategies targeting inflammation in microvessel occlusive complications of SCD, and the potential clinical use of hs-CRP as a biomarker in childhood SCD.

Application of the comet assay for assessment of oxidative DNA damage in circulating lymphocytes of Tetralogy of Fallot patients.

Tetralogy of Fallot (TOF) is a common and severe cyanotic congenital heart defect characterized by frequent episodes of hypoxia due to cyanosis. The hypoxia of cyanotic heart disease results in a down-regulation of antioxidant defenses, making cells vulnerable to oxidant damage, which subsequently leads to the single strand breaks and oxidative DNA damage. Quantification of DNA damage was performed in circulating lymphocytes of Tetralogy of Fallot patients (n=63) and healthy controls (n=65). The damage of DNA was assessed by alkaline comet assay in lymphocytes isolated from all children followed by silver staining. The DNA migrates out of the nucleus forming a tail, which represents the extent of DNA damage in individual cells. TOF patients exerted a higher percent of comet tails, which are indicative of DNA damage, when compared to control children (p<0.001). The mean comet tail length was significantly higher in TOF patients (2.57+/-0.29) when compared with healthy controls (1.28+/-0.32). The results showed that hypoxia is associated with an increase in the level of oxidants and a simultaneous decrease in the level of antioxidants in patients. Hence, the present study concludes unequivocally that hypoxia causes oxidative DNA damage in TOF patients.

Bilateral uveitis in a patient with autoimmune lymphoproliferative syndrome.

PURPOSE: We report a case of autoimmune lymphoproliferative syndrome (ALPS) presenting with bilateral uveitis. DESIGN: Observational case report. METHODS: Review of case record, serum and aqueous IL-10 and IL-6 cytokine results, and immunosuppressive treatment of a patient with a mutation in the gene encoding Fas. RESULTS: Control of the intermediate uveitis required sustained doses of topical and periocular corticosteroids as well as systemic cyclosporine. The serum IL-10 level was elevated, as commonly seen in ALPS, but the aqueous IL-10 was not. CONCLUSIONS: Despite a Th2 immune predominance in ALPS, uveitis, a Th1-mediated disease, may still manifest in these patients. The pathogenesis of uveitis in ALPS may differ from that of the systemic disease overall. Long-term follow-up is required for patients with uveitis associated with ALPS.