Dimitrios Chanouzas

Intravenous Cyclophosphamide and Plasmapheresis in Dialysis-Dependent ANCA-Associated Vasculitis

BACKGROUND AND OBJECTIVES Induction therapy with oral cyclophosphamide (CYP) has been a mainstay of treatment in patients with severe renal failure secondary to ANCA-associated vasculitis (AAV). Recent evidence proposes using pulsed intravenous CYP in less severe disease to minimize adverse events. It is unclear if this can be translated to those with dialysis-dependent renal insufficiency. DESIGN, SETTING, PARTICIPANTS, & METHODS All AAV patients presenting between 2005 and 2010 requiring dialysis at presentation were retrospectively analyzed. Patients were treated with plasma exchange, corticosteroids, and intravenous CYP. Rate of dialysis independence at 3 and 12 months and adverse effects were assessed and compared with the outcome of the plasmapheresis, prednisolone, and oral CYP arm of the randomized MEPEX (methylprednisolone versus plasma exchange) trial. RESULTS Forty-one patients were included. At 3 months, 3 (7.3%) patients had died on dialysis, 12 (29.3%) remained dialysis dependent, and 26 (63.4%) were dialysis independent (creatinine, 2.5 mg/dl; GFR, 26 ml/min per 1.73 m(2)). Four patients subsequently reached ESRD at a median time of 83 days. Thirty-seven (90%) patients reached 1 year follow-up, 13 (35%) remained dialysis dependent, and 24 (65%) had independent renal function. Eleven patients (27%) had episodes of leukopenia (white cell count <4×10(9)/L) during CYP therapy and 17 (41%) experienced infectious complications. This compares favorably with the dialysis-dependent cohort treated with plasmapheresis in the MEPEX study in which 51% were alive with independent renal function at 1 year. CONCLUSIONS Intravenous CYP used with corticosteroids and plasmapheresis may be an effective alternative to oral CYP in patients with dialysis-dependent AAV.

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

BackgroundThe 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/designCANVAS 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.DiscussionThe 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 registrationClinicalTrials.gov Identifier NCT01633476 (registered 29 June 2012).

Genetic variation at the CD28 locus and its impact on expansion of pro-inflammatory CD28 negative T cells in healthy individuals

The CD28 locus is associated with susceptibility to a variety of autoimmune and immune-mediated inflammatory diseases including primary sclerosing cholangitis (PSC). Previously, we linked the CD28 pathway in PSC disease pathology and found that vitamin D could maintain CD28 expression. Here, we assessed whether the PSC-associated CD28 risk variant A (rs7426056) affects CD28 expression and T cell function in healthy individuals (n = 14 AA, n = 14 AG, n = 14 GG). Homozygotes for the PSC disease risk allele (AA) showed significantly lower CD28 mRNA expression ex-vivo than either GG or AG (p < 0.001) in total peripheral blood mononuclear cells. However, the CD28 risk variant alone was not sufficient to explain CD28 protein loss on CD4+ T cells. All genotypes responded equally to vitamin D as indicated by induction of a regulatory phenotype and an increased anti-inflammatory/pro-inflammatory cytokine ratio. A genotypic effect on response to TNFα stimuli was detected, which was inhibited by vitamin D. Together our results show: (a) an altered gene expression in carriers of the susceptible CD28 variant, (b) no differences in protein levels on CD4+ T cells, and (c) a protective effect of the variant upon CD28 protein loss on CD4+ T cells under inflammatory conditions.

Glucocorticoid activation by 11β‐hydroxysteroid dehydrogenase enzymes in relation to inflammation and glycaemic control in chronic kidney disease: a cross‐sectional study

Patients with chronic kidney disease (CKD) have dysregulated cortisol metabolism secondary to changes in 11β‐hydroxysteroid dehydrogenase (11β‐HSD) enzymes. The determinants of this and its clinical implications are poorly defined.

The host cellular immune response to cytomegalovirus targets the endothelium and is associated with increased arterial stiffness in ANCA-associated vasculitis

BackgroundCardiovascular disease is a leading cause of death in ANCA-associated vasculitis (AAV). An expansion of CD4+CD28null T cells is seen mainly in cytomegalovirus (CMV)-seropositive individuals and has been linked to increased cardiovascular disease risk in other conditions. The aims of this study were to phenotype CD4+CD28null T cells in AAV with respect to their pro-inflammatory capacity and ability to target and damage the endothelium and to investigate their relationship to arterial stiffness, a marker of cardiovascular mortality.MethodsCD4+CD28null T cells were phenotyped in 53 CMV-seropositive AAV patients in stable remission and 30 age-matched CMV-seropositive healthy volunteers by flow cytometry following stimulation with CMV lysate. The expression of endothelial homing markers and cytotoxic molecules was evaluated in unstimulated CD4+CD28null T cells. Arterial stiffness was measured by carotid-to-femoral pulse wave velocity (PWV) in patients with AAV.ResultsCD4+CD28null T cells were CMV-specific and expressed a T helper 1 (Th1) phenotype with high levels of interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α) secretion. They also co-expressed the endothelial homing markers CX3CR1, CD49d and CD11b and cytotoxic molecules perforin and granzyme B. CD4+CD28null T cells were phenotypically similar in patients with AAV and healthy volunteers but their proportion was almost twice as high in patients with AAV (11.3% [3.7–19.7] versus 6.7 [2.4–8.8]; P = 0.022). The size of the CD4+CD28null T-cell subset was independently linked to increased PWV in AAV (0.66 m/s increase per 10% increase in CD4+CD28null cells, 95% confidence interval 0.13–1.19; P = 0.016).ConclusionThe host cellular immune response to CMV leads to the expansion of cytotoxic CD4+CD28null T cells that express endothelial homing markers and are independently linked to increased arterial stiffness, a marker of cardiovascular mortality. Suppression of CMV in AAV may be of therapeutic value in reducing the risk of cardiovascular disease.