Clinical trial parameters that influence outcomes in lupus trials that use the systemic lupus erythematosus responder index

Objective: The SLE Responder Index (SRI) is a composite endpoint used in SLE trials. This investigation examined the clinical trial elements that drive response measured by the SRI. Methods: Analyses are based on data from two phase 3 trials (n = 2262) that evaluated the impact of an anti-B-cell activating factor antibody on disease activity using SRI-5 as the primary endpoint (ClinicalTrials.gov NCT01196091 and NCT01205438). Results: The SRI-5 response rate at week 52 for all patients was 32.8%. Non-response due to a lack of SLEDAI improvement, concomitant medication non-compliance or dropout was 31, 16.5 and 19.1%, respectively. Non-response due to deterioration in BILAG or Physician's Global Assessment after SLEDAI improvement, concomitant medication compliance and trial completion was 0.5%. Disease activity in three SLEDAI organ systems was highly prevalent at baseline: mucocutaneous, 90.6%; musculoskeletal, 82.9%; and immunologic, 71.6%. Disease activity in each of the other organ systems was <11% of patients. Four clinical manifestations were highly prevalent at baseline: arthritis, 82.6%; rash, 69.2%; alopecia, 58.2%; and mucosal ulcer, 32.5%. The combined prevalence of renal, vascular and CNS disease at baseline was 17.6%; these patients had high SRI-5 response rates. Adjustments to corticosteroids were allowed during the first 24 weeks. Increases in corticosteroids above 2.5 mg/day were observed in 16.2% of placebo patients over the first 24 weeks after randomization. Conclusion: The primary drivers of SRI-5 response were SLEDAI improvement, concomitant medication adherence and trial completion. Arthritis, rash, alopecia and mucosal ulcer were the most prevalent clinical manifestations at baseline. Corticosteroid increases and rare, highly weighted disease manifestations in SLEDAI can confound the SRI signal

Suppression and Regression of Choroidal Neovascularization in Mice by a Novel CCR2 Antagonist, INCB3344

PURPOSE: To investigate the effect of an intravitreally administered CCR2 antagonist, INCB3344, on a mouse model of choroidal neovascularization (CNV). METHODS: CNV was induced by laser photocoagulation on Day 0 in wild type mice. INCB3344 or vehicle was administered intravitreally immediately after laser application. On Day 14, CNV areas were measured on retinal pigment epithelium (RPE)-choroid flat mounts and histopathologic examination was performed on 7 µm-thick sections. Macrophage infiltration was evaluated by immunohistochemistry on RPE-choroid flat mounts and quantified by flow cytometry on Day 3. Expression of vascular endothelial growth factor (VEGF) protein in RPE-choroid tissue was examined by immunohistochemistry and ELISA, VEGF mRNA in sorted macrophages in RPE-choroid tissue was examine by real-time PCR and expression of phosphorylated extracellular signal-regulated kinase (p-ERK 1/2) in RPE-choroid tissue was measured by Western blot analysis on Day 3. We also evaluated the efficacy of intravitreal INCB3344 to spontaneous CNV detected in Cu, Zn-superoxide dismutase (SOD1) deficient mice. Changes in CNV size were assessed between pre- and 1week post-INCB3344 or vehicle administration in fundus photography and fluorescence angiography (FA). RESULTS: The mean CNV area in INCB3344-treated mice decreased by 42.4% compared with the vehicle-treated control mice (p<0.001). INCB3344 treatment significantly inhibited macrophage infiltration into the laser-irradiated area (p<0.001), and suppressed the expression of VEGF protein (p = 0.012), VEGF mRNA in infiltrating macrophages (p<0.001) and the phosphorylation of ERK1/2 (p<0.001). The area of spontaneous CNV in Sod1⁻/⁻ mice regressed by 70.35% in INCB3344-treated animals while no change was detected in vehicle-treated control mice (p<0.001). CONCLUSIONS: INCB3344 both inhibits newly forming CNV and regresses established CNV. Controlling inflammation by suppressing macrophage infiltration and angiogenic ability via the CCR-2/MCP-1 signal may be a useful therapeutic strategy for treating CNV associated with age-related macular degeneration

Vampires in the village Žrnovo on the island of Korčula: following an archival document from the 18th century

Središnja tema rada usmjerena je na raščlambu spisa pohranjenog u Državnom arhivu u Mlecima (fond: Capi del Consiglio de’ Dieci: Lettere di Rettori e di altre cariche) koji se odnosi na događaj iz 1748. godine u korčulanskom selu Žrnovo, kada su mještani – vjerujući da su se pojavili vampiri – oskvrnuli nekoliko mjesnih grobova. U radu se podrobno iznose osnovni podaci iz spisa te rečeni događaj analizira u širem društvenom kontekstu i prate se lokalna vjerovanja.The main interest of this essay is the analysis of the document from the State Archive in Venice (file: Capi del Consiglio de’ Dieci: Lettere di Rettori e di altre cariche) which is connected with the episode from 1748 when the inhabitants of the village Žrnove on the island of Korčula in Croatia opened tombs on the local cemetery in the fear of the vampires treating. This essay try to show some social circumstances connected with this event as well as a local vernacular tradition concerning superstitions