Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases; pathomechanisms that regulate extravasation of damaging immune cells into surrounding tissues are poorly ...understood. Here we identified three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation. Two patients developed liver fibrosis in their first year of life. Next-generation sequencing identified two de novo truncating variants in the Src-family tyrosine kinase, LYN, p.Y508*, p.Q507* and a de novo missense variant, p.Y508F, that result in constitutive activation of Lyn kinase. Functional studies revealed increased expression of ICAM-1 on induced patient-derived endothelial cells (iECs) and of β2-integrins on patient neutrophils that increase neutrophil adhesion and vascular transendothelial migration (TEM). Treatment with TNF inhibition improved systemic inflammation; and liver fibrosis resolved on treatment with the Src kinase inhibitor dasatinib. Our findings reveal a critical role for Lyn kinase in modulating inflammatory signals, regulating microvascular permeability and neutrophil recruitment, and in promoting hepatic fibrosis.
Abstract
In previous studies we have shown that the healthy murine ocular surface is colonized by a commensal, Corynebacterium mastitidis, that elicits IL-17 from γδ T cells and promotes local host ...defense. Based on that, we hypothesized that ocular inflammation in patients with NLRP3-associated mutations, including those with Cryopyrin Associated Periodic Syndrome (CAPS), may be triggered by an overactive response to their own eye surface commensals. We found that, unlike wild type mice, mice with a CAPS mutant NLRP3 gene and increased IL-1β and IL-17 responses, develop conjunctival neutrophilia and ocular inflammation following ocular exposure to C. mast. Single cell transcriptomics confirmed that conjunctival γδ T cells were the major source of IL-17 and identified increased amounts of ccr2 and s100a8 mRNA, accounting for the neutrophil infiltration. In parallel studies of patients with inflammasome-associated mutations (NLRP3 or CARD8 mutations) we found that patient PBMCs cultured with C. mast produced increased amounts of IL-17A compared to healthy controls (C. mast. status of subjects: unknown). Patient immune cells (conjunctival and PBMC) showed upregulation of RORC, BATF and STAT3 as well as interferon-related genes (IRF1, STAT1). However, unlike in mice, IL-17-related genes appeared to be more upregulated in αβ than in γδ T cells, suggesting that in patients this response may be mediated by other cells, and/or that other commensals than in mice may be the stimulus. Thus, commensals can elicit an exaggerated immune response in humans and mice with NLRP3-related autoinflammatory disease. If indeed the conjunctivitis in CAPS patients reflects a response to their own commensals, adjunct antimicrobial therapy may be considered.
Objective
To assess the clinical value of 18F‐fluorodeoxyglucose (FDG) positron emission tomography (PET) in a prospective cohort of patients with large vessel vasculitis (LVV) and comparator ...subjects.
Methods
Patients with Takayasu arteritis and giant cell arteritis were studied, along with a comparator group consisting of patients with hyperlipidemia, patients with diseases that mimic LVV, and healthy controls. Participants underwent clinical evaluation and FDG‐PET imaging, and patients with LVV underwent serial imaging at 6‐month intervals. We calculated sensitivity and specificity of FDG‐PET interpretation for distinguishing patients with clinically active LVV from comparator subjects and from patients with disease in clinical remission. A qualitative summary score based on global arterial FDG uptake, the PET Vascular Activity Score (PETVAS), was used to study associations between activity on PET scan and clinical characteristics and to predict relapse.
Results
A total of 170 FDG‐PET scans were performed in 115 participants (56 patients with LVV and 59 comparator subjects). FDG‐PET distinguished patients with clinically active LVV from comparator subjects with a sensitivity of 85% (95% confidence interval 95% CI 69, 94) and a specificity of 83% (95% CI 71, 91). FDG‐PET scans were interpreted as active vasculitis in most patients with LVV in clinical remission (41 of 71 58%). Clinical disease activity status, disease duration, body mass index, and glucocorticoid use were independently associated with activity on PET scan. Among patients who underwent PET during clinical remission, future clinical relapse was more common in patients with a high PETVAS than in those with a low PETVAS (55% versus 11%; P = 0.03) over a median follow‐up period of 15 months.
Conclusion
FDG‐PET provides information about vascular inflammation that is complementary to, and distinct from, clinical assessment in LVV. FDG‐PET scan activity during clinical remission was associated with future clinical relapse.
To assess the clinical value of
F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in a prospective cohort of patients with large vessel vasculitis (LVV) and comparator subjects.
Patients ...with Takayasu arteritis and giant cell arteritis were studied, along with a comparator group consisting of patients with hyperlipidemia, patients with diseases that mimic LVV, and healthy controls. Participants underwent clinical evaluation and FDG-PET imaging, and patients with LVV underwent serial imaging at 6-month intervals. We calculated sensitivity and specificity of FDG-PET interpretation for distinguishing patients with clinically active LVV from comparator subjects and from patients with disease in clinical remission. A qualitative summary score based on global arterial FDG uptake, the PET Vascular Activity Score (PETVAS), was used to study associations between activity on PET scan and clinical characteristics and to predict relapse.
A total of 170 FDG-PET scans were performed in 115 participants (56 patients with LVV and 59 comparator subjects). FDG-PET distinguished patients with clinically active LVV from comparator subjects with a sensitivity of 85% (95% confidence interval 95% CI 69, 94) and a specificity of 83% (95% CI 71, 91). FDG-PET scans were interpreted as active vasculitis in most patients with LVV in clinical remission (41 of 71 58%). Clinical disease activity status, disease duration, body mass index, and glucocorticoid use were independently associated with activity on PET scan. Among patients who underwent PET during clinical remission, future clinical relapse was more common in patients with a high PETVAS than in those with a low PETVAS (55% versus 11%; P = 0.03) over a median follow-up period of 15 months.
FDG-PET provides information about vascular inflammation that is complementary to, and distinct from, clinical assessment in LVV. FDG-PET scan activity during clinical remission was associated with future clinical relapse.
For reasons poorly understood, and despite the availability of biological medications blocking IL-1 and IL-6 that have markedly improved overall disease control, children with Systemic Juvenile ...Idiopathic Arthritis (SJIA) are now increasingly diagnosed with life-threatening chronic complications, including hepatitis and lung disease (SJIA-LD). On October 3-4, 2019, a two-day meeting, NextGen Therapies for Systemic Juvenile Idiopathic Arthritis (SJIA) & macrophage activation syndrome (MAS) organized by the Systemic JIA Foundation (www.systemicjia.org/) in Washington, DC brought together scientists, clinicians, parents and FDA representatives with the objectives (1) to integrate clinical and research findings in MAS and SJIA-LD, and (2) to develop a shared understanding of this seemingly new pulmonary complication of SJIA. The current manuscript summarizes discussions and conclusions of the meeting. Keywords: Systemic juvenile idiopathic arthritis, Macrophage activation syndrome, Hemophagocytic lymphohistiocytosis, Interferonopathy, Interstitial lung disease, Pulmonary alveolar proteinosis, Alveolar macrophages
Abstract Objective To evaluate short-term ureteral catheterization in patients undergoing ureteroscopic lithotripsy for ureteral calculi. Methods Patients ( n = 140) with ureteral calculi who were ...candidates for ureterolithotripsy were enrolled. Stone size was 5–10 mm. The operation was performed with an 8–9.8F semirigid ureteroscope without active dilatation and stones were fragmented with a 1F pneumatic lithotrite. Uncomplicated cases (109 patients) were randomized to catheterized (C) and noncatheterized (NC) groups. In the 54 C group patients, a polyurethane catheter (5F) was passed through the ureter after lithotripsy with the end attached to a Foley placed in urethra, which was removed after 24 h. Postoperatively, all patients were evaluated for flank and suprapubic pain, renal colic, irritative urinary symptoms, peritonism, frequency of analgesic usage, urinary tract infection, duration of hospitalization, postdischarge visits (due to renal colic/pain), readmission, and residual stone rates. Results On the first postoperative day, the percentage of patients experiencing flank pain and renal colic was significantly higher in the NC group (76% and 45%) compared with the C group (20% and 2%); 67% of NC patients required analgesic administration during hospital stay versus 20% of C patients ( p < 0.001). Suprapubic pain and urethral irritation were reported by 13% and 37% of C patients, respectively, and 5% and 4% of NC patients. However, peritonism was developed more often in NC patients (27% vs. 13%). Hospital stay was 1 d for all patients. Three days postoperatively, 40% of NC patients complained of at least one episode of flank pain compared with 7% of C patients ( p < 0.001). Incidence of urinary tract infections was 4% in NC and 7% in C group patients. Postdischarge visits were necessary in 20% of NC patients and 5% of C patients. No patient in either group required readmission. No complaints were reported nor residual stones discovered on 2-wk follow-up radiographs in either group. Conclusions Short-term ureteral catheterization in uncomplicated ureteroscopy and lithotripsy has a role in reducing early postoperative morbidities. It may also decrease pain and colic after discharge.
Thrombus formation during endovascular embolization of intracranial aneurysms occurs in 2.9%-6% of patients. Use of IIb/IIIA inhibitors such as abciximab or eptifibatide intravenously has been ...reported in management of this complication. Because the intra-arterial infusion of IIb/IIIA inhibitors may require lower doses to achieve thrombolysis, it may reduce the risk of haemorrhage. Therefore, we retrospectively analyze our database and review the literature.
This is a retrospective analysis of a prospectively acquired database of patients with ruptured or unruptured aneurysm treated intra-arterially for thrombus formation during endovascular coil embolization between July 2005 and August 2008. Patient demographics, aneurysmal characteristics, procedural, clinical outcome and complications were recorded.
From July 2005 to August 2008, out of 184 patients who underwent coil embolization, 19 patients (15 smokers, 14 female, mean age 52) developed intraprocedural thrombus formation and received intra-arterial abciximab treatment. Mean aneurysm size was 6.6 mm±4.9 mm; neck size was 3.8 mm±2.1 mm. Eight (42.1%) aneurysms were ruptured. Most aneurysms (63.1%) were in anterior communicating and middle cerebral arteries. Thrombus was visualized in all cases by angiogram and treated intra-arterially with a mean dose of 10.5 mg±4.2. There were no periprocedural hemorrhagic complications. No deaths or other complications occurred during follow-up.
Thrombus formation during coil embolization of intracranial aneurysms occurred more in women and smokers. Low doses of intra-arterial abciximab may be effective in the thromboembolic complications occurring during endovascular embolization of intracranial aneurysms.
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