Defining the neutrophil phenotype in systemic sclerosis

Background: Systemic sclerosis (SSc) is a disease characterised by a triad of immunological abnormalities, endothelial cell dysfunction and fibrosis. Neutrophils are the most abundant circulating leukocyte. They contain several mediators which when released can lead to modulation of the inflammatory response, cause endothelial cell activation and injury and eventually lead to fibrosis. The peri-endothelial cell environment in SSc has the potential to lead to neutrophil activation and indeed this has been previously described in the literature in terms of reactive oxygen species (ROS) generation. In this thesis I aim to explore the hypothesis that: “Neutrophils are activated in SSc and contribute to endothelial cell activation and damage”. Methods: The functional phenotype of SSc neutrophils was explored in vitro. Functions investigated included; ROS generation, chemotaxis, integrin expression, apoptosis and CD16 expression. The protein expression of ex vivo SSc neutrophils was compared to healthy control neutrophils. The DIGE technology was used to explore the pan-proteome and iTRAQ was used to focus in on the plasma membrane proteome. The role of neutrophil elastase was explored in SSc by examining the serum neutrophil elastase concentration and activity and correlating these to clinical manifestations of disease. The role of neutrophil: endothelial cell interactions was modelled in vitro using live cell imaging by confocal microscopy looking for evidence of endothelial cell activation (E-selectin expression) and apoptosis. Experiments examined the role of neutrophil derived mediators in these interactions. Results: Functional studies revealed that SSc neutrophils are hypofunctional in terms of spontaneous ROS generation and chemotaxis in vitro. This may reflect in vivo activation. SSc neutrophils are similar in terms of integrin expression and baseline apoptosis to control neutrophils. Pan-proteomic studies reveal neutrophil activation in SSc since changes in protein expression mirror those seen in response to neutrophil activators TNFα and LPS. Proteomic studies also point to neutrophil priming in vivo. Serum neutrophil elastase concentrations and activity were not elevated in SSc, however, discrepancies between concentration and activity suggest a functional deficiency in elastase inhibitors in SSc serum. Serum elastase activity and concentrations were found to be lower in RNP (ribonucleoprotein) positive patients indicating that different mechanisms maybe involved in different SSc subtypes. In vitro models demonstrate that SSc serum causes endothelial cell activation and apoptosis and that neutrophils are essential for this effect. Serine proteases seem to play an important role in inducing apoptosis and IL-6 trans signalling is involved in endothelial cell activation and apoptosis. Neutrophils do not express IL-6 but are dominant sources of the soluble IL-6R which is essential for trans signalling. Conclusions: There is evidence that neutrophils are activated in SSc though; no specific activating signature is identified. In co-cultures, neutrophils are essential for endothelial cell activation and apoptosis in response to SSc serum. Neutrophil mediators including serine proteases and IL6R are likely to play important roles in this effect. Therefore neutrophils may play an important part in the propagation of inflammation and endothelial cell activation which eventually leads to the fibrotic phenotype which is characteristic of this disease

The Many Faces of Interleukin-6: The Role of IL-6 in Inflammation, Vasculopathy, and Fibrosis in Systemic Sclerosis

Interleukin-6 is currently attracting significant interest as a potential therapeutic target in systemic sclerosis (SSc). In this paper, the biology of interleukin-6 is reviewed, and the evidence for interleukin-6 dysregulation in SSc is explored. The role of inteleukin-6 classical and trans signalling pathways in SSc relevant phenomena such as chronic inflammation, autoimmunity, endothelial cell dysfunction, and fibrogenesis is discussed. The existing evidence that interventions designed to block interleukin-6 signalling are of therapeutic relevance in SSc is evaluated

The value of embedded secondary-care-based psychology services in rheumatology: an exemplar for long-term conditions

Rheumatoid arthritis is an exemplar long term condition, complicated by pain, disability, co-morbidities and long term medication use. It has significant effects on mobility, work performance, social role, sexual function and relationships. It is commonly associated with fatigue and mood disturbance as a result of complex interactions of physical (disease related) and psychosocial factors. NICE guidance recommends the availability of psychological support for these patients. We have implemented a psychology service for our patients with chronic rheumatological conditions. This study was set up to capture the value of this service

Big events, little change: Extreme climatic events have no region-wide effect on Great Barrier Reef governance

Extreme climatic events trigger changes in ecosystems with potential negative impacts for people. These events may provide an opportunity for environmental managers and decision-makers to improve the governance of social-ecological systems, however there is conflicting evidence regarding whether these actors are indeed able to change governance after extreme climatic events. In addition, the majority of research to date has focused on changes in specific policies or organizations after crises. A broader investigation of governance actors’ activities is needed to more fully understand whether or not crises trigger change. Here we demonstrate the use of a social network analysis of management and decision-making forums (e.g. meetings, partnerships) to reveal the effects of an extreme climatic event on governance of the Great Barrier Reef over an eight-year period. To assess potential shifts in action, we examine the topics of forums and the relative participation and influence of diverse governance actors before, during, and after two back-to-back mass coral bleaching events in 2016 and 2017. Our analysis reveals that there is little change in the topics that receive attention, and in the relative participation and influence of different actor groups in the region. Our research demonstrates that network analysis of forums is useful for analyzing whether or not actors’ activities and priorities evolve over time. Our results provide empirical evidence that governance actors struggle to leverage extreme climate events as windows of opportunity and further research is needed to identify alternative opportunities to improve governance

Biologic monotherapy in the biologic naive patient with rheumatoid arthritis (RA): results from an observational study

In the original article, the corresponding author's given name and middle name were interchanged

Pharmacy study of natural health product adverse reactions (SONAR): a cross-sectional study using active surveillance in community pharmacies to detect adverse events associated with natural health products and assess causality

OBJECTIVES: To investigate the rates and causality of adverse event(s) (AE) associated with natural health product (NHP) use, prescription drug use and concurrent NHP-drug use through active surveillance in community pharmacies. DESIGN: Cross-sectional study of screened patients. SETTING: 10 community pharmacies across Alberta and British Columbia, Canada from 14 January to 30 July 2011. PARTICIPANTS: The participating pharmacy staff screened consecutive patients, or agents of patients, who were dropping or picking up prescription medications.PRIMARY OUTCOME MEASURES: Patients were screened to determine the proportions of them using prescription drugs and/or NHPs, as well as their respective AE rates. All AEs reported by the screened patients who took a NHP, consented to, and were available for, a detailed telephone interview (14%) were adjudicated fully to assess for causality.RESULTS: Over a total of 105 pharmacy weeks and 1118 patients screened, 410 patients reported taking prescription drugs only (36.7%; 95% CI 33.9% to 39.5%), 37 reported taking NHPs only (3.3%; 95% CI 2.4% to 4.5%) and 657 reported taking prescription drugs and NHPs concurrently (58.8%; 95% CI 55.9% to 61.6%). In total, 54 patients reported an AE, representing 1.2% (95% CI 0.51% to 2.9%), 2.7% (95% CI 0.4% to 16.9%) and 7.3% (95% CI 5.6% to 9.6%) of each population, respectively. Compared with patients who reported using prescription drugs, the patients who reported using prescription drugs and NHPs concurrently were 6.4 times more likely to experience an AE (OR; 95% CI 2.52 to 16.17; p<0.001). Combined with data from Ontario, Canada, a national proportion was calculated, which found that 45.4% (95% CI 43.8% to 47.0%) of Canadians who visit community pharmacies take NHPs and prescription drugs concurrently, and of those, 7.4% (95% CI 6.3% to 8.8%) report an AE.CONCLUSIONS: A substantial proportion of community pharmacy patients use prescription drugs and NHPs concurrently; these patients are at a greater risk of experiencing an AE. Active surveillance provides a means of detecting such AEs and collecting high-quality data on which causality assessment can be based

Hepatitis B virus (HBV) viral load, liver and renal function in adults treated with tenofovir disoproxil fumarate (TDF) vs. untreated:a retrospective longitudinal UK cohort study

Abstract Background Current clinical guidelines recommend treating chronic hepatitis B virus (HBV) infection in a minority of cases, but there are relatively scarce data on evolution or progression of liver inflammation and fibrosis in cases of chronic HBV (CHB) that do not meet treatment criteria. We aimed to assess the impact of TDF on liver disease, and the risk of renal impairment in treated CHB patients in comparison to untreated patients. Methods We studied a longitudinal ethnically diverse CHB cohort in the UK attending out-patient clinics between 2005 and 2018. We examined TDF treatment (vs. untreated) as the main exposure, with HBV DNA viral load (VL), ALT, elastography scores and eGFR as the main outcomes, using paired tests and mixed effects model for longitudinal measurements. Additionally, decline of eGFR during follow-up was quantified within individuals by thresholds based on clinical guidelines. Baseline was defined as treatment initiation for TDF group and the beginning of clinical follow-up for untreated group respectively. Results We included 206 adults (60 on TDF, 146 untreated), with a median ± IQR follow-up duration of 3.3 ± 2.8 years. The TDF group was significantly older (median age 39 vs. 35 years, p = 0.004) and more likely to be male (63% vs. 47%, p = 0.04) compared to the untreated group. Baseline difference between TDF and untreated groups reflected treatment eligibility criteria. As expected, VL and ALT declined significantly over time in TDF-treated patients. Elastography scores normalised during treatment in the TDF group reflecting regression of inflammation and/or fibrosis. However, 6/81 (7.4%) of untreated patients had a progression of fibrosis stage from F0-F1 to F2 or F3. There was no evidence of difference in rates or incidence of renal impairment during follow-up in the TDF vs. untreated group. Conclusions Risk of liver inflammation and fibrosis may be raised in untreated patients compared to those receiving TDF, and TDF may benefit a larger percentage of the CHB population