Real-World Six- and Twelve-Month Drug Retention, Remission, and Response Rates of Secukinumab in 2,017 Patients With Psoriatic Arthritis in Thirteen European Countries

Objective There is a lack of real-life studies on interleukin-17 (IL-17) inhibition in psoriatic arthritis (PsA). We assessed real-life 6- and 12-month effectiveness (i.e., retention, remission, low disease activity [LDA], and response rates) of the IL-17 inhibitor secukinumab in PsA patients overall and across 1) number of prior biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), 2) years since diagnosis, and 3) European registries. Methods Thirteen quality registries in rheumatology participating in the European Spondyloarthritis Research Collaboration Network provided longitudinal, observational data collected as part of routine care for secondary use. Data were pooled and analyzed with Kaplan-Meier plots, log rank tests, Cox regression, and multiple linear and logistic regression analyses. Results A total of 2,017 PsA patients started treatment with secukinumab between 2015 and 2018. Overall secukinumab retention rates were 86% and 76% after 6 and 12 months, respectively. Crude (LUNDEX adjusted) 6-month remission/LDA (LDA including remission) rates for the 28-joint Disease Activity Index for Psoriatic Arthritis, the Disease Activity Score in 28 joints using the C-reactive protein level, and the Simplified Disease Activity Index (SDAI) were 13%/46% (11%/39%), 36%/55% (30%/46%), and 13%/56% (11%/47%), and 12-month rates were 11%/46% (7%/31%), 39%/56% (26%/38%), and 16%/62% (10%/41%), respectively. Clinical Disease Activity Index remission/LDA rates were similar to the SDAI rates. Six-month American College of Rheumatology 20%/50%/70% improvement criteria responses were 34%/19%/11% (29%/16%/9%); 12-month rates were 37%/21%/11% (24%/14%/7%). Secukinumab effectiveness was significantly better for b/tsDMARD-naive patients, similar across time since diagnosis (4 years), and varied significantly across the European registries. Conclusion In this large real-world study on secukinumab treatment in PsA, 6- and 12-month effectiveness was comparable to that in previous observational studies of tumor necrosis factor inhibitors. Retention, remission, LDA, and response rates were significantly better for b/tsDMARD-naive patients, were independent of time since diagnosis, and varied significantly across the European countries.Peer reviewe

Increased ERCC1 expression is linked to chromosomal aberrations and adverse tumor biology in prostate cancer

Abstract Background Animal model experiments have suggested a role of the DNA repair protein ERCC1 (Excision Repair Cross-Complementation Group 1) in prostate cancer progression. Methods To better understand the impact of ERCC1 protein expression in human prostate cancer, a preexisting tissue microarray (TMA) containing more than 12,000 prostate cancer specimens was analyzed by immunohistochemistry and data were compared with tumor phenotype, PSA recurrence and several of the most common genomic alterations (TMPRSS2:ERG fusions: deletions of PTEN, 6q, 5q, 3p). Results ERCC1 staining was seen in 64.7% of 10,436 interpretable tissues and was considered weak in 37.1%, moderate in 22.6% and strong in 5% of tumors. High-level ERCC1 staining was linked to advanced pT stage, high Gleason grade, positive lymph nodes, high pre-operative serum PSA, and positive surgical margin status (p < 0.0001 each). High ERCC1 expression was strongly associated with an elevated risk of PSA recurrence (p < 0.0001). This was independent of established prognostic features. A subgroup analysis of cancers defined by comparable quantitative Gleason grades revealed that the prognostic impact was mostly driven by low-grade tumors with a Gleason 3 + 3 or 3 + 4 (Gleason 4: ≤5%). High ERCC1 expression was strongly associated with the presence of genomic alterations and expression levels increased with the number of deletions present in the tumor. These latter data suggest a functional relationship of ERCC1 expression with genomic instability. Conclusion The results of our study demonstrate that expression of ERCC1 - a potential surrogate for genomic instability - is an independent prognostic marker in prostate cancer with particular importance in low-grade tumors

Belimumab in Autoimmune Liver Diseases with associated Sjögren’s Syndrome

Background: B cell-activating factor (BAFF) levels are elevated in autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC). About 20% of patients with PBC and 5% with AIH have a Sjögren’s syndrome (SjS). PBC and SjS have many features in common. Belimumab (anti-BAFF) shows positive effects in SjS. Methods: Retrospective analysis on treatment response to belimumab in three female patients with AIH and/or PBC with SjS. Patient 1: 52y, with AIH (F2), PBC and SjS. Indication: active AIH with intolerance to standard treatment; belimumab since 01/20. Patient 2: 72y, with PBC (F3) and SjS. Indication: refractory PBC; belimumab since 11/20. Patient 3: 54y, with PBC (F2, ductopenia), SjS and erosive rheumatoid arthritis. Indication: refractory PBC; belimumab since 11/20. Results: Patient 1: AIH in remission under belimumab monotherapy. Patient 2: PBC in remission 6 months after treatment start. Patient 3: Cholestasis stable. Slight decrease of mildly elevated transaminases and almost normalization of IgM. The effects on SjS were overall encouraging in all patients. Conclusions: These preliminary findings indicate belimumab as a promising treatment option in AIH and PBC, with so far no safety concerns. Our study shows how the occurrence of different autoimmune diseases can guide us to further personalize treatment and highlights the strengths of a tight collaboration between hepatology and rheumatolog

Belimumab in Autoimmune Liver Diseases with associated Sjögren’s Syndrome

Background: Autoimmune hepatitis (AIH) is an auto-inflammatory disease of the liver with, if untreated, a high mortality rate. About 75% of patients are responsive to synthetic disease modifying drugs (sDMARD). Primary biliary cholangitis (PBC) is an inflammatory disease of small and medium sized bile ducts. Despite standard treatments (ursodeoxycholic acid (UDCA), fibrates and obeticholic acid (OCA)), a significant proportion of patients has progressive disease. Twenty percent of PBC patients have Sjögren’s syndrome (SjS). PBC has many features in common with SjS: epidemiology, epithelitis, well-characterized autoantibodies and a poor response to immunosuppressive treatments. Hypothesis: Based on the increased B cell-activating factor (BAFF) levels in AIH, PBC and SjS patients and the similarities between PBC and SjS, we hypothesized that belimumab is effective in AIH and PBC. Methods: Retrospective analysis of treatment responses to belimumab in three female patients with AIH and/or PBC with moderate to advanced liver fibrosis and concomitant SjS. Patient 1: 52y, with AIH, PBC and SjS. Indication: active AIH with intolerance to previous treatments (AZA, MMF, rituximab); belimumab since 01/20. Patient 2: 72y, with PBC and SjS. Indication: refractory PBC despite UDCA and fibrates (OCA declinedby health insurance); belimumab since 11/20. Patient 3: 54y, with PBC (with ductopenia), SjS and erosive rheumatoid arthritis (RA). RA responding insufficiently to all commonly used sDMARDs and biologicals. She was on low dose steroids, HCQ and etanercept. Her PBC was active despite UDCA and fibrates (OCA not tolerated). Indication: refractory PBC; belimumab since 11/20. We discontinued etanercept, when belimumab was started. Results: Patient 1: Remission of AIH under belimumab. Patient 2: Remission of PBC after 6 months of belimumab. Patient 3: Stable cholestasis parameters. Improvement of slightly elevated transaminases and almost normalization of IgM. Improvement of sicca symptoms in all patients. Two patients had a transient improvement in fatigue. RA in patient 3 remained on a level of moderate disease activity. Conclusions: These preliminary findings suggest belimumab as a promising treatment option in AIH and PBC, with so far no safety concerns. Our study shows how the basket of autoimmune diseases can guide us to evaluate new drug candidates in a more efficient way and highlights the strengths of a tight collaboration between hepatology and rheumatology

Functional Activity of Plasmid DNA after Entry into the Atmosphere of Earth Investigated by a New Biomarker Stability Assay for Ballistic Spaceflight Experiments

Sounding rockets represent an excellent platform for testing the influence of space conditions during the passage of Earth's atmosphere and re-entry on biological, physical and chemical experiments for astrobiological purposes. We designed a robust functionality biomarker assay to analyze the biological effects of suborbital spaceflights prevailing during ballistic rocket flights. During the TEXUS-49 rocket mission in March 2011, artificial plasmid DNA carrying a fluorescent marker (enhanced green fluorescent protein: EGFP) and an antibiotic resistance cassette (kanamycin/neomycin) was attached on different positions of rocket exterior; (i) circular every 90 degree on the outer surface concentrical of the payload, (ii) in the grooves of screw heads located in between the surface application sites, and (iii) on the surface of the bottom side of the payload. Temperature measurements showed two major peaks at 118 and 130°C during the 780 seconds lasting flight on the inside of the recovery module, while outer gas temperatures of more than 1000°C were estimated on the sample application locations. Directly after retrieval and return transport of the payload, the plasmid DNA samples were recovered. Subsequent analyses showed that DNA could be recovered from all application sites with a maximum of 53% in the grooves of the screw heads. We could further show that up to 35% of DNA retained its full biological function, i.e., mediating antibiotic resistance in bacteria and fluorescent marker expression in eukariotic cells. These experiments show that our plasmid DNA biomarker assay is suitable to characterize the environmental conditions affecting DNA during an atmospheric transit and the re-entry and constitute the first report of the stability of DNA during hypervelocity atmospheric transit indicating that sounding rocket flights can be used to model the high-speed atmospheric entry of organics-laden artificial meteorites

Cohort profile: SCREEN-RA: design, methods and perspectives of a Swiss cohort study of first-degree relatives of patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is an insidious autoimmune disease, with an immunological onset years before diagnosis. Early interventions in preclinical stages could prevent or minimise the progression towards irreversible joint damage. The SCREEN-RA cohort (Evaluation of a SCREENing strategy for Rheumatoid Arthritis) aims to characterise the preclinical stages of the disease, to identify environmental risk factors, and to discover or validate novel biomarkers predictive for RA development

Scanning electron microscopy (SEM).

<p>The surface of the TEXUS payload was analyzed by SEM 50 µg of DNA in Tris buffer was applied and air dried. As controls the same volume of Tris buffer was applied and air dried and additionally the structure was analyzed without an application of fluid. The DNA Tris buffer mixture forms a thick film that completely fills the grooves with a width and a height of approximately 100 µm and 21 µm, respectively. Arrows indicate the location where DNA or Tris buffer solution was applied.</p

Locations of DNA application on the TEXUS-49 payload.

<p><b>a</b> Scheme of the TEXUS-49 payload with DNA sample 1–12 application sites <b>b</b> Plasmid DNA samples 1–12 were applied on the outside of the TEM (TEXUS Experiment Module) EML 4 <b>.cI</b> DNA samples 1–4 were applied circular at 0, 90, 180, 270 degree directly on the surface of the payload. DNA samples 5–12 were also applied with a distance of 90 degree each in the screw heads of the payload <b>.cII</b> DNA samples 13–15 were applied directly on the payload surface at the bottom side <b>.d</b> DNA samples 1–4 were pipetted directly on the surface and locations were marked with a pen <b>.e</b> DNA samples 5–12 were applied in the grooves of the screw heads <b>.f</b> DNA samples 13–15 were applied directly on the payload surface on the bottom side and locations were marked with a pen.</p