Cytomegalovirus modulation of the immune system in ANCA associated vasculitis

Infection and cardiovascular disease represent the two most important sources of mortality in ANCA associated vasculitis (AAV). Expansions of CD4+CD28null T-cells that are only present in cytomegalovirus (CMV) positive individuals have previously been associated with increased infection and mortality in AAV, and cardiovascular disease in other inflammatory diseases. The work described in this thesis examines the hypothesis that subclinical CMV reactivation in AAV drives the expansion of CD4+CD28null T-cells thereby leading to the observed adverse outcomes. To investigate this, a proof of concept clinical trial of 6 months valaciclovir treatment or no additional therapy was designed and implemented in CMV seropositive AAV patients in remission. Valaciclovir treatment successfully blocked CMV reactivation and in turn this led to a reduction in the proportion of CD4+CD28null T-cells in the treated patients together with favourable changes in other associated CMV induced changes on the immune system. CD4+CD28null T-cells in AAV were identified as Th1, proinflammatory cytotoxic T-cells, able to target endothelial cells and were independently associated with increased arterial stiffness, an established marker of cardiovascular risk. These findings implicate subclinical CMV reactivation as a potentially reversible cause of vascular pathology in inflammatory disease and open novel therapeutic opportunities

Cocaine-induced granulomatosis with polyangiitis—an under-recognized condition

Objectives: Cocaine and cocaine mixed with levamisole are increasingly used in the UK and result in significant direct nasal damage in addition to promoting vasculitis. Our aims were as follows: (1) to identify the main symptoms and presentation of cocaine-induced vasculitis; (2) to provide evidence regarding the best practice for the investigation and diagnosis of cocaine-induced vasculitis; and (3) to analyse the clinical outcomes of patients in order to understand the optimal management for the condition./ Methods: We performed a retrospective case series analysis of patients presenting with cocaine-induced midline destructive lesions or vasculitis compatible with granulomatosis with polyangiitis (GPA) from two large tertiary vasculitis clinics between 2016 and 2021./ Results: Forty-two patients (29 Birmingham, 13 London) with cocaine-induced midline lesions or systemic disease were identified. The median age was 41 years (range 23–66 years). Current cocaine use was common, and 20 of 23 samples provided were positive when routine urine toxicology was performed; 9 patients who denied ever using cocaine were identified as using cocaine based on urine toxicology analysis, and 11 who stated they were ex-users still tested positive. There was a high incidence of septal perforation (75%) and oronasal fistula (15%). Systemic manifestations were less common (27%), and only one patient had acute kidney injury. Fifty-six per cent of our patients were PR3-ANCA positive, with none testing positive for MPO-ANCA. Symptom remission required cocaine discontinuation even when immunosuppression was administered./ Conclusion: Patients with destructive nasal lesions, especially young patients, should have urine toxicology performed for cocaine before diagnosing GPA and considering immunosuppressive therapy. The ANCA pattern is not specific for cocaine-induced midline destructive lesions. Treatment should be focused on cocaine cessation and conservative management in the first instance in the absence of organ-threatening disease

Treatment of fatigue with physical activity and behavioural change support in vasculitis: Study protocol for an open-label randomised controlled feasibility study

© 2018 Author(s) (or their employer(s)). Introduction Fatigue is a major cause of morbidity, limiting quality of life, in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). The aetiology of fatigue is multifactorial; biological and psychosocial mediators, such as sleep deprivation, pain and anxiety and depression, are important and may be improved by increasing physical activity. Current self-management advice is based on expert opinion and is poorly adhered to. This study aims to investigate the feasibility of increasing physical activity using a programme of direct contact and telephone support, to provide patient education, encourage behaviour self-monitoring and the development of an individual change plan with defined goals and feedback to treat fatigue compared with standard of care to inform the design of a large randomised controlled trial to test the efficacy and cost effectiveness of this programme. Methods and analysis Patients with AAV and significant levels of fatigue (patient self-report using multidimensional fatigue index score questionnaire ≥14) will be randomised in a 1:1 ratio to the physical activity programme supported by behavioural change techniques or standard of care. The intervention programme will consist of 8 visits of supervised activity sessions and 12 telephone support calls over 12 weeks with the aim of increasing physical activity to the level advised by government guidelines. Assessment visits will be performed at baseline, 12, 24 and 52 weeks. The study will assess the feasibility of recruitment, retention, the acceptability, adherence and safety of the intervention, and collect data on various assessment tools to inform the design of a large definitive trial. A nested qualitative study will explore patient experience of the trial through focus groups or interviews. Ethics and dissemination All required ethical and regulatory approvals have been obtained. Findings will be disseminated through conference presentations, patient networks and academic publications

CD28null CD4 T-cell expansions in autoimmune disease suggest a link with cytomegalovirus infection

Immunosenescence is thought to contribute to the increase of autoimmune diseases in older people. Immunosenescence is often associated with the presence of an expanded population of CD4 T cells lacking expression of CD28 (CD28null). These highly cytotoxic CD4 T cells were isolated from disease-affected tissues in patients with rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, or other chronic inflammatory diseases and their numbers appeared to be linked to disease severity. However, we recently demonstrated that the common herpes virus, cytomegalovirus (CMV), not ageing, is the major driver of this subset of cytotoxic T cells. In this review, we discuss how CMV might potentiate and exacerbate autoimmune disease through the expansion of CD28null CD4 T cells

ANCA-associated vasculitis.

The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are a group of disorders involving severe, systemic, small-vessel vasculitis and are characterized by the development of autoantibodies to the neutrophil proteins leukocyte proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA). The three AAV subgroups, namely granulomatosis with polyangiitis (GPA), microscopic polyangiitis and eosinophilic GPA (EGPA), are defined according to clinical features. However, genetic and other clinical findings suggest that these clinical syndromes may be better classified as PR3-positive AAV (PR3-AAV), MPO-positive AAV (MPO-AAV) and, for EGPA, by the presence or absence of ANCA (ANCA+ or ANCA-, respectively). Although any tissue can be involved in AAV, the upper and lower respiratory tract and kidneys are most commonly and severely affected. AAVs have a complex and unique pathogenesis, with evidence for a loss of tolerance to neutrophil proteins, which leads to ANCA-mediated neutrophil activation, recruitment and injury, with effector T cells also involved. Without therapy, prognosis is poor but treatments, typically immunosuppressants, have improved survival, albeit with considerable morbidity from glucocorticoids and other immunosuppressive medications. Current challenges include improving the measures of disease activity and risk of relapse, uncertainty about optimal therapy duration and a need for targeted therapies with fewer adverse effects. Meeting these challenges requires a more detailed knowledge of the fundamental biology of AAV as well as cooperative international research and clinical trials with meaningful input from patients

Valaciclovir to prevent Cytomegalovirus mediated adverse modulation of the immune system in ANCA-associated vasculitis (CANVAS):study protocol for a randomised controlled trial

BACKGROUND: The ANCA-associated vasculitides (AAV) are systemic autoimmune inflammatory disorders characterised by necrotising inflammation affecting small to medium-sized blood vessels. Despite improvements in survival, infection and cardiovascular disease remain leading causes of morbidity and mortality. Considerable evidence suggests that CD4 + CD28null T-cell expansions, predominantly seen in Cytomegalovirus (CMV) seropositive individuals, are associated with systemic dysregulation of immune function leading to a heightened risk of infection and cardiovascular disease. In patients with AAV, CD4 + CD28null expansions are driven by CMV and are associated with an increased risk of infection and mortality. The aim of this study is to explore in detail the ways in which CMV modulates the immune system and to determine whether treatment with valaciclovir blocks subclinical CMV reactivation in CMV seropositive AAV patients and ameliorates the CMV-induced adverse effects on the immune system. METHODS/DESIGN: CANVAS is a single-centre prospective open-label randomised controlled proof-of-concept trial of 50 adult CMV seropositive patients with stable AAV. Participants will be randomly allocated to receive valaciclovir orally (2 g QDS or reduced according to renal function) or no additional treatment for 6 months with an additional 6-month follow-up period. The primary outcome is the proportion of patients with CMV reactivation, as assessed by measurable viral load on quantitative blood and urine CMV polymerase chain reaction. The secondary outcomes are safety, change in the proportion of CD4+ CMV-specific T-cell population (defined as CD4 + CD28null cells) and change in soluble markers of inflammation from baseline to 6 months. Further tertiary and exploratory outcomes include persistence of the effect of valaciclovir on the proportion of CD4 + CD28null cells at 6 months post completion of treatment, change in the immune phenotype of CD4+ T cells and change in blood pressure and arterial stiffness parameters from baseline to 6 months. DISCUSSION: The results of this study will enable larger studies to be conducted to determine whether by controlling subclinical CMV reactivation, we can improve clinical endpoints such as infection and cardiovascular disease. The potential impact of this study is not limited to AAV, as CD4 + CD28null cells have been linked to adverse outcomes in other inflammatory conditions and in the context of an ageing immune system. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01633476 (registered 29 June 2012). ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13063-016-1482-2) contains supplementary material, which is available to authorized users

Timing of acute kidney injury--does it matter? A single-centre experience from the United Kingdom.

BACKGROUND Acute kidney injury (AKI) requiring renal replacement therapy (RRT) is associated with high mortality and long-term dependence on RRT. However, there is limited information about the difference in outcome between patients who develop AKI in the community (c-AKI), and those who develop AKI in hospital (h-AKI). AIM Identify differences in short- and long-term outcomes between patients admitted with c-AKI and h-AKI who require intermittent haemodialysis, and to identify factors that predict poor outcome. DESIGN & METHODS Single-centre, retrospective analysis of 306 patients with AKI who received intermittent haemodialysis between 2009 and 2011. FOLLOW-UP six months. Primary endpoints: patient and renal survival. Secondary endpoints: time on dialysis, length of hospital stay, and admission to the intensive care unit (ICU). RESULTS Survival for patients in the h-AKI group was significantly lower, at 42.9% (compared to 72%). They had a significantly longer length of stay. However, at 6-month follow-up, the survival benefit of the c-AKI group was no longer significant. Patients with h-AKI were more likely to be dialysis independent at discharge and six months although this result did not reach statistical significance. Independent predictors of survival to discharge within the entire group included: renal/post-renal causes of AKI, younger age, pre-existing diabetes, and c-AKI. The only independent predictor for RRT dependence at discharge and six months was pre-existing chronic kidney disease. CONCLUSIONS h-AKI is associated with high mortality and longer hospital stays during the acute admission. However, h-AKI patients who survive are more likely to be independent of RRT at discharge and follow-up

Improving Acute Kidney Injury (AKI) outcomes through the use of automated electronic alerts.

We read the letter of Cheshire et al. [1] with interest, in response to our recent publication “Timing of acute kidney injury — does it matter? A single-centre experience from the United Kingdom” [2]. In our analysis, we only examined patients who ultimately required a period of renal replacement therapy (RRT) at some point during their hospital admission. Hence, the hospital-acquired acute kidney injury (h-AKI) group inherently had normal renal function at presentation whilst the distribution of the AKIN stages within the community acquired acute kidney injury (c-AKI) group was different to what would be expected when all patients admitted with acute kidney injury (AKI) are examined irrespective of whether they require RRT or not

Le Travailleur de l'Etat : organe de l'Union fédérative des travailleurs de l'Etat

novembre 19331933/11 (N374)