Efficacy and safety of tenofovir alafenamide (taf) vs tenofovir disoproxil fumarate (tdf) in east asian chronic hepatitis b patients following 5-years of treatment [Meeting Abstract]
Background Pivotal studies GS-US-320-0108 (HBeAg-negative) and GS-US-320-0110 (HBeAg-positive), demonstrated non-inferior antiviral efficacy of TAF vs. TDF with superior renal/ bone safety through 5-years, after up to 3 years of doubleblind (
Eosinophilic fasciitis in children: Clinical course and response to treatment from two large academic centers [Meeting Abstract]
Background/Purpose: Eosinophilic fasciitis (EF) is a rare connective tissue disease characterized by a progressive inflammatory thickening of skin and soft tissues. The diagnosis is based on clinical features, imaging, and biopsy findings. Due to limited experience with pediatric disease, diagnosis and treatment are often challenging. We describe our longitudinal experience in treating children with EF. Methods: This is a retrospective study where data were collected on clinical features, laboratory results at diagnosis, disease course, and treatment response. Descriptive statistics were used where appropriate. Results: Our series includes 7 patients with EF, with a mean age at diagnosis of 12.4 (+/- 5.1) years and a mean follow-up of 45.1 months (Table 1). All patients had peripheral eosinophilia. Three patients had elevated serum aldolase, one had elevated creatine kinase, and two had abnormal thyroid function at diagnosis. Six patients had typical biopsy features of eosinophilic infiltration of the fascial layer with inflammatory infiltrates. The remaining patient had non-specific inflammation on biopsy. (Table presented) Treatment induction in all patients consisted of high-dose intravenous solumedrol with subsequent oral prednisone or intravenous solumedrol. All patients required methotrexate (MTX) for disease control and 4 required addition of mycophenolate mofetil (MMF). Time to first improvement in any clinical symptom was 3.4 months. Improvement in skin findings and laboratory abnormalities was noted in all patients after treatment with intravenous solumedrol. Two patients had disease flares. Case 1 had recurrent flares of arthritis at 4 months after steroid wean and after 2.5 months of MTX wean. Case 2 flared with skin lesions after 12 months of MTX wean. Chronic complications included lipodystrophy (3 patients), leg length discrepancy (1), and joint contractures (3) [elbows and ankles (1) and fingers (2)]. Conclusion: Pediatric EF is challenging to diagnose and treat, mainly due to its rarity and lack of homogeneous clinical experience. This is the largest pediatric case series reported in the last 10 years. Our data show a higher prevalence of distal limb involvement, Raynaud's phenomenon and asymmetric disease in children, possibly exhibiting a phenotype distinct from classic adult EF. Systemic or visceral involvement was absent in our patients. Our data confirm the efficacy of corticosteroid as first-line therapy, and suggest a role for MTX as a promising steroidsparing agent. Our patients often experienced a more severe disease progression compared to adults, requiring escalation of therapy to include one or more steroid-sparing agents. In refractory cases, addition of MMF in our series showed optimistic results leading to remission of EF symptoms
Adenoviral-mediated gene transfer of ICP47 inhibits major histocompatibility complex class I expression on vascular cells in vitro
PURPOSE: Many viruses have evolved mechanisms to evade detection by the host immune system. The herpes simplex gene ICP47 encodes a protein that binds to the host antigen-processing transporter, inhibiting the formation of major histocompatibility complex class I (MHC-I) antigens in infected cells. MHC-I antigen expression is also important in acute allograft rejection. This study was designed to quantitate the effect of adenoviral-mediated gene transfer of ICP47 on MHC-I cell surface expression of human vascular cells. We hypothesized that the transduction of vascular cells with a replication-incompetent adenoviral vector that was expressing ICP47 (AdICP47) would inhibit constitutive and inducible MHC-I expression and thereby reduce the rate of cytolysis of ICP47-transduced vascular cells by sensitized cytotoxic T lymphocytes (CTL). METHODS: A replication-incompetent adenoviral vector, AdICP47, was created to express ICP47 driven by the cytomegalovirus immediate early promoter. Cultured human vascular endothelial and smooth muscle cells and human dermal fibroblasts were transduced with either AdICP47 or the control empty vector AddlE1. Cell surface constitutive and gamma-interferon-induced MHC-I expression were quantitated by flow cytometry. A standard 4-hour chromium release cytotoxicity assay was used to determine the percent cytolysis of transduced and nontransduced endothelial cells by sensitized CTL. Finally, to quantitate the specificity of the effect of ICP47 on MHC-I expression, adhesion molecule expression was quantitated in both transduced and nontransduced cells. RESULTS: Constitutive MHC-I expression in AdICP47-transduced endothelial cells was inhibited by a mean of 84% +/- 5% (SEM) in five experiments. After 48 hours of exposure to gamma-interferon, AdICP47-transduced cells exhibited a mean of 66% +/- 8% lower MHC-I expression than nontransduced cells. Similar inhibition in MHC-I expression was achieved in AdICP47-transduced vascular smooth muscle cells and dermal fibroblasts. Percent cytolysis of AdICP47-transduced endothelial cells by CTL was reduced by 72%. Finally, the specificity of the effect of transduction of ICP47 on vascular cell MHC-I expression was confirmed by a lack of significant change in either constitutive or tumor necrosis factor-induced vascular cell adhesion molecule/intercellular adhesion molecule expression. CONCLUSION: Transduction of vascular cells with AdICP47 strongly inhibits both constitutive and inducible MHC-I expression in human vascular cells. AdICP47-transduced cells exhibited a substantial reduction in cytolysis by CTL. Thus AdICP47 transduction holds promise as a technique to characterize the role of MHC-I expression in acute vascular allograft rejection in vivo and as a potential therapeutic intervention.