13 research outputs found
The role of inflammation in systemic sclerosis
Systemic sclerosis (SSc) is a connective tissue disease of unknown etiology. It is a rare disorder with an incidence in adults of approximately 20 new cases per million per year (1). Genetic and environmental factors such as toxins and infections have been identified to be associated with SSc (2, 3). Its pathogenesis is characterized by vasculopathy, autoimmunity, and cytokine dysbalance, altogether leading to fibrosis of the skin and inner organs (4). These features vary between patients, but it seems clear that SSc pathogenesis is characterized by a complex interplay between these factors. There is a high heterogeneity in clinical presentation of SSc e.g. limited versus diffuse SSc, early vs. chronic disease, or early vs. late onset SSc, that have to be taken into consideration when studying this disease (5). Along the important progress in inflammation research that has been made during the last decade in general, inflammation has also attracted increasing attention in SSc (6). Both the innate and adaptive immune system participates in SSc pathogenesis. The importance of the immune system in SSc has also been demonstrated in cases where SSc patients underwent autologous or allogeneic stem cell transplantation. Conditioning e.g. with cyclophosphamide followed by reinfusion of stem cells markedly improved the disease course (7). Cell infiltrates in SSc affected dermis mainly consist of T- and B lymphocytes, macrophages, and mast cells. These cells release profibrotic mediators which then stimulate fibroblasts to secrete extracellular matrix (ECM) proteins (8-10). The inflammatory cells are responsible for a profibrotic cytokine milieu, typically characterized by Th2 cytokines (11). Humoral autoimmunity in the form of autoantibodies has been postulated to contribute to SSc progression, e.g. by autoantibodies against endothelial cells or fibroblasts (12). Although B-cells clearly occur in the inflamed SSc tissue and certainly are of importance, the pathogenic relevance of autoantibodies in SSc remains controversial (13). This work contributes to the understanding of SSc by further analyses of the cellular pathogenesis and cytokines involved in SSc. Both experimental and clinical studies have been performed in this thesis, analysing different inflammatory cell types and cytokines and patient subgroups, respectively.EThOS - Electronic Theses Online ServiceGBUnited Kingdo
Scleroderma and related disorders: 223. Long Term Outcome in a Contemporary Systemic Sclerosis Cohort
Background: We have previously compared outcome in two groups of systemic sclerosis (SSc) patients with disease onset a decade apart and we reported data on 5 year survival and cumulative incidence of organ disease in a contemporary SSc cohort. The present study examines longer term outcome in an additional cohort of SSc followed for 10 years. Methods: We have examined patients with disease onset between years 1995 and 1999 allowing for at least 10 years of follow-up in a group that has characteristics representative for the patients we see in contemporary clinical practice. Results: Of the 398 patients included in the study, 252 (63.3%) had limited cutaneous (lc) SSc and 146 (36.7%) had diffuse cutaneous (dc) SSc. The proportion of male patients was higher among the dcSSc group (17.1% v 9.9%, p = 0.037) while the mean age of onset was significantly higher among lcSSc patients (50 ± 13 v 46 ± 13 years ± SD, p = 0.003). During a 10 year follow-up from disease onset, 45% of the dcSSc and 21% of the lcSSc subjects developed clinically significant pulmonary fibrosis, p < 0.001. Among them approximately half reached the endpoint within the first 3 years (23% of dcSSc and 10% of lcSSc) and over three quarters within the first 5 years (34% and 16% respectively). There was a similar incidence of pulmonary hypertension (PH) in the two subsets with a steady rate of increase over time. At 10 years 13% of dcSSc and 15% of lcSSc subjects had developed PH (p=0.558), with the earliest cases observed within the first 2 years of disease. Comparison between subjects who developed PH in the first and second 5 years from disease onset demonstrated no difference in demographic or clinical characteristics, but 5-year survival from PH onset was better among those who developed this complication later in their disease (49% v 24%), with a strong trend towards statistical significance (p = 0.058). Incidence of SSc renal crisis (SRC) was significantly higher among the dcSSc patients (12% v 4% in lcSSc, p = 0.002). As previously observed, the rate of development of SRC was highest in the first 3 years of disease- 10% in dcSSc and 3% in lcSSc. All incidences of clinically important cardiac disease developed in the first 5 years from disease onset (7% in dcSSc v 1% in lcSSc, p < 0.001) and remained unchanged at 10 years. As expected, 10-year survival among lcSSc subjects was significantly higher (81%) compared to that of dcSSc patients (70%, p = 0.006). Interestingly, although over the first 5 years the death rate was much higher in the dcSSc cohort (16% v 6% in lcSSc), over the following years it became very similar for both subsets (14% and 13% between years 5 and 10, and 18% and 17% between years 10 and 15 for dcSSc and lcSSc respectively). Conclusions: Even though dcSSc patients have higher incidence for most organ complications compared to lcSSc subjects, the worse survival among them is mainly due to higher early mortality rate. Mortality rate after first 5 years of disease becomes comparable in the two disease subsets. Disclosure statement: The authors have declared no conflicts of interes
Using an onion like neutron scattering instrument model to quickly optimize design parameters
Venous Thromboembolism Prophylaxis with Rivaroxaban in Elective Foot and Ankle Surgery
Category: Other Introduction/Purpose: Oral application for prophylaxis of venous thromboembolism (VTE) after total hip and knee arthroplasty has high acceptance among patients due to its non-invasive nature, when compared to traditional subcutaneous application of low- molecular-weight heparin (LMWH). Approximately 10% of the patients in our clinic receive oral thrombosis prophylaxis (rivaroxaban), the remaining patients receive subcutaneous prophylaxis with LMWH (dalteparin). However, no clinical data exists describing the use of oral prophylaxis in elective orthopedic foot and ankle surgery. The aims of this study where: 1. To assess the incidence of VTE after oral prophylaxis after elective foot and ankle procedures. 2. To identify risk factors for VTE after oral prophylaxis after elective foot and ankle procedures. Methods: A retrospective chart review of patients undergoing elective foot and ankle surgery between January 2010 and 2013 was performed. The type of medicamentous thrombosis prophylaxis was noted. All patients receiving oral antithrombotic medication (rivaroxaban, Xarelto©, Bayer, Germany) were included in the study. Location, length and type of surgery and tourniquet time were assessed. Co-morbidities (e.g. diabetes, coagulopathy, ASA classification) were noted. Patients previously treated with phenprocoumon or clopidrogel were excluded. A phone interview was performed and patients were asked whether a thromboembolic incident occurred or not. If an incidence was confirmed, the report of the diagnostic findings was obtained from the general practitioner. Results: 450 patients were included. Two thromboembolic incidents occurred (0.4%; deep venous thrombosis confirmed by ultrasound). Both patients had a history of previous deep venous thrombosis and a positive family history for VTE. Due to the low percentage of patients with VTE, a multivariate analysis could not be performed. Conclusion: The incidence of VTE after oral thrombosis prophylaxis with rivaroxaban is low and comparable with the incidence after subcutaneous application of LMWH
Green tea extract to prevent colorectal adenomas in men and women : Results of the MIRACLE trial
Long-term surveillance of biologic therapies in systemic-onset juvenile idiopathic arthritis: data from the German BIKER registry
Objective. Using data from the German Biologics JIA Registry (BIKER), long-term safety of biologics for systemic-onset JIA with regard to adverse events of special interest was assessed. Methods. Safety assessments were based on adverse event reports after first dose through 90 days after last dose. Rates of adverse event, serious adverse event and 25 predefined adverse events of special interest were analysed. Incidence rates were compared for each biologic against all other biologics combined applying a mixed-effect Poisson model. Results. Of 260 systemic-onset JIA patients in this analysis, 151 patients received etanercept, 109 tocilizumab, 71 anakinra and 51 canakinumab. Patients with etanercept had higher clinical Juvenile Arthritis Disease Activity Score 10 scores, active joint counts and steroid use at therapy start. Serious adverse events were reported with higher frequency in patients receiving canakinumab [20/100 patient years (PY)] and tocilizumab (21/100 PY). Cytopenia and hepatic events occurred with a higher frequency with tocilizumab and canakinumab. Medically important infections were seen more often in patients with IL-6 or IL-1 inhibition. Macrophage activation syndrome occurred in all cohorts with a higher frequency in patients with canakinumab (3.2/100 PY) and tocilizumab (2.5/100 PY) vs anakinra (0.83/100 PY) and etanercept (0.5/100 PY). After adjustment only an elevated risk for infections in anakinra-treated patients remained significant. Three definite malignancies were reported in patients ever exposed to biologics. Two deaths occurred in patients treated with etanercept. Conclusion. Surveillance of pharmacotherapy as provided by BIKER is an import approach especially for patients on long-term treatment. Overall, tolerance was acceptable. Differences between several biologics were noted and should be considered in daily patient care
Experiences with IL-1 blockade in systemic juvenile idiopathic arthritis - data from the German AID-registry
BackgroundSystemic juvenile idiopathic arthritis (sJIA) is a complex disease with dysregulation of the innate immune system driven by cytokines. A major role is ascribed to interleukin-1 beta (IL-1 beta), supporting the autoinflammatory character of the disease and offering an effective blocking mechanism for treatment. Here we present clinical practice data from the German AID-registry for patients treated with IL-1 inhibition (IL-1i).MethodsIn 2009 a clinical and research consortium (AID-Net) was established, including an online AID-registry. Patients with documented sJIA diagnosis were identified. Data for this retrospective IL-1i study were recorded by 17 centers. Response to treatment was evaluated according to Wallace criteria and additionally by an own classifying clinical response system.ResultsIn 6years, 202 patients with confirmed sJIA were recorded in the AID-registry. Out of these, 111 children received therapy with Anakinra (ANA) (n=84, 39 f) and/or Canakinumab (CANA) (n=27, 15 f) at a median age of 8.7 y (range 0.6-19.1). During the first 12months 75/111 (ANA 55, CANA 20) patients were evaluated according to Wallace criteria (achievement of inactive disease 28/55 and 17/20, remission over 6months under medication 13/55 and 7/20 cases). Over the whole period of time, clinical response was preserved in the majority of patients (ANA 54/80, CANA 20/27). Arthritis mostly persisted in polyarticular (PA) courses. During treatment with IL-1i concomitant medication could be tapered in about 15%. IL-1i was discontinued in 59/111 patients. 45 (15) adverse events (AE)s in ANA (CANA) treated patients (19.7 (26.6) AE/100 ANA (CANA) exposure years, 95%CI: 14.4-26.4 (14.9-43.9)) were reported.ConclusionIn a large cohort of sJIA patients from Germany, we can confirm an overall favorable clinical response to both available IL-1 blocking agents. IL-1i was well tolerated with acceptable safety and effectiveness in a real-life clinical setting
Response-adapted lenalidomide maintenance in newly diagnosed myeloma: results from the phase III GMMG-MM5 trial
The MM5 trial aimed at demonstrating a progression-free survival (PFS) difference in continued vs. response-adapted (in case of complete response, CR) lenalidomide (LEN) maintenance therapy (MT) in newly diagnosed, transplant-eligible multiple myeloma (MM). Patients were equally randomized to receive induction therapy with PAd (bortezomib/doxorubicin/dexamethasone) or VCD (bortezomib/cyclophosphamide/dexamethasone), high-dose melphalan and autologous blood stem cell transplantation, and LEN consolidation, followed by either LEN MT for a fixed duration of 2 years (LEN-2Y) or until achievement of CR (LEN-CR, intention-to-treat population n = 502): arms A1:PAd + LEN-2Y (n = 125), B1:PAd + LEN-CR (n = 126), A2:VCD + LEN-2Y (n = 126), B2:VCD + LEN-CR (n = 125). In the LEN-CR group (B1 + B2), n = 88/17.5% patients did not start or discontinued LEN MT due to CR. There was no PFS (p = 0.60, primary endpoint) nor overall survival (OS) (p = 0.15) difference between the four study arms. On pooled LEN MT strategies, OS (hazard ratio, hazard ratio [HR] = 1.42, p = 0.03) but not PFS (HR = 1.15, p = 0.20) was shorter in LEN-CR (B1 + B2) vs. LEN-2Y (A1 + A2) groups. PFS was shortened on landmark analyses from the start of LEN MT in patients being in CR in the LEN-CR group (LEN-CR vs. LEN-2Y, HR = 1.84, p = 0.02). OS from first progression was shortened in the LEN-CR vs. LEN-2Y group (HR = 1.60, p = 0.01). LEN MT should be applied beyond CR for at least 2 years