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1.
QJM ; 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31613364

RESUMO

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of early death in patients with chronic kidney disease (CKD). Previous work has described an association between CMV seropositivity and cardiovascular disease amongst patients with dialysis dependent end stage renal disease. Whether CMV seropositivity is associated with cardiovascular disease in non-dialysis dependent CKD has not been established. AIM: Investigate whether past CMV infection is associated with prevalent cardiovascular disease in patients with non-dialysis dependent CKD. DESIGN: A retrospective observational study using the Renal Impairment in Secondary Care (RIISC) cohort, a study evaluating bio-clinical determinants of outcomes in patients with progressive CKD. METHODS: We assayed cryopreserved serum samples collected at inception for anti-CMV IgG antibodies from 764 patients with stages 2 to 5 CKD (pre-dialysis) and investigated its relationship with prevalent cardiovascular disease. RESULTS: Median eGFR was 24 ml/min/1.73m2 (IQR 19-32). Sixty-eight percent of patients were CMV seropositive. CMV seropositivity was associated with older age, non-Caucasian ethnicity, diabetes and higher social deprivation index score. On univariable analysis, CMV seropositivity correlated with higher systolic blood pressure (p = 0.044), prevalent cardiovascular disease (p < 0.001), ischaemic heart disease (p < 0.001) and cerebrovascular disease (p = 0.022). On multivariable analysis, CMV seropositive patients nearly twice as likely to have cardiovascular disease compared to seronegative patients (OR = 1.998, CI 1.231-3.242, p = 0.005). CONCLUSIONS: In patients with non-dialysis CKD, CMV seropositivity is independently associated with a higher prevalence of cardiovascular disease.

2.
J Rheumatol ; 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31263068

RESUMO

OBJECTIVE: Fatigue is common and burdensome in ANCA-associated vasculitis (AAV). This study aimed to understand how fatigue changes over time following treatment initiation and determine whether individuals with the poorest prognosis can be robustly identified. METHODS: 149 patients with AAV and new onset disease recruited to two clinical trials (RITUXIVAS and MYCYC) were followed for 18 months. Fatigue was measured at baseline and 6 monthly intervals using the vitality domain of the SF-36 quality of life questionnaire and compared to a cohort of 470 controls. Group-based trajectory modelling (GBTM) determined trajectories of the symptom between which baseline characteristics and on-going fatigue scores were compared. RESULTS: Fatigue levels at diagnosis were worse in patients than controls (median 30 IQR 10, 48 vs 70 IQR 55, 80; p<0.001), with 46% of patients reporting severe fatigue. Fatigue improved after 6 months treatment but remained worse than controls (p<0.001). GBTM revealed varied trajectories of fatigue: low fatigue stable (n=23), moderate baseline fatigue improver (n=29), high baseline fatigue improver (n=61) and stable baseline high fatigue (n=37). Participants who followed stable high fatigue trajectories had lower vasculitis activity compared to improvers but no other demographic or clinical variables differed. CONCLUSION: This study longitudinally measured fatigue levels in patients with AAV. Although, most patients improve following treatment, an important subgroup of patients report persistent high levels of fatigue that does not change. Few clinical or laboratory markers distinguished these patients, suggesting alternative interventions specific for fatigue are required.

3.
J Rheumatol ; 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31308208

RESUMO

OBJECTIVE: Age is a risk factor for organ damage, adverse events, and mortality in microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). However, the relationship between treatment and damage, hospitalizations, and causes of death in elderly patients is largely unknown. METHODS: Consecutive patients from Sweden, England, and the Czech Republic diagnosed between 1997 and 2013 were included. Inclusion criteria were a diagnosis of MPA or GPA and age 75 years or more at diagnosis. Treatment with cyclophosphamide, rituximab, and corticosteroids the first three months was registered. Outcomes up to two years from diagnosis included vasculitis damage index (VDI), hospitalization, and cause of death. RESULTS: Treatment data was available for 167 of 202 patients. At two years, 4% had no items of damage. There was a positive association between VDI score at two years and Birmingham Vasculitis Activity Score at onset, and a negative association with treatment using cyclophosphamide or rituximab. Intravenous methylprednisolone dose was associated with treatment-related damage. During the first year, 69% of patients were readmitted to hospital. MPO-ANCA positivity and lower creatinine levels decreased the odds for readmission. The most common cause of death was infection, and this was associated with cumulative oral prednisolone dose. CONCLUSION: Immunosuppressive treatment with cyclophosphamide or rituximab in elderly patients with MPA and GPA was associated with development of less permanent organ damage and was not associated with hospitalization. However, higher doses of corticosteroids during the first three months was associated with treatment-related damage and fatal infections.

4.
Front Immunol ; 10: 1405, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31297110

RESUMO

Proteinuria has been identified as prognosticator of renal outcome in patients with ANCA-associated glomerulonephritis, but whether proteinuria is related to podocyte abnormalities in these patients is largely unknown. We here investigate podocyte foot process width and number of podocytes positive for the podocyte marker WT-1 in diagnostic renal biopsies of 25 Caucasian patients with ANCA-associated glomerulonephritis in relation to proteinuria. Control tissue was used from pre-transplantation donor kidney biopsies. Proteinuria at 10 weeks follow-up correlated significantly with foot process width (P = 0.04). Biopsies with foot process width ≥600 nm belonged more often to the crescentic or mixed class, whereas biopsies with a foot process width <600 nm were most often categorized as focal class (P = 0.03). The mean number of podocytes based upon expression of WT-1 was significantly lower in patients compared to controls (15 vs. 34 podocytes per glomerulus; P < 0.0001). The significant decrease in expression of the podocyte WT-1 marker in ANCA-associated glomerulonephritis is considered indicative of actual podocyte loss or at least, of a loss of functionality. Furthermore, our study indicates that podocyte foot process width at baseline could be indicative for proteinuria at short term follow up. For prognostic purposes, we therefore suggest to include a description of the foot process width in the diagnostic report of a biopsy with ANCA-associated glomerulonephritis.

6.
BMC Nephrol ; 20(1): 154, 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31060510

RESUMO

BACKGROUND: Glucocorticoids (GCs) are frequently used to treat glomerular diseases but are associated with multiple adverse effects including hypothalamic-pituitary-adrenal axis inhibition that can lead to adrenal insufficiency (AI) on withdrawal. There is no agreed GC tapering strategy to minimise this risk. METHODS: This is a single centre retrospective study, between 2013 to 2016, of patients with glomerular disease on GC therapy for more than 3 months screened for GC induced AI with short synacthen stimulation tests (SSTs) done prior to complete GC withdrawal. We investigated the prevalence of AI, predictors, choice of screening tool and recovery. RESULTS: Biochemical evidence of GC induced AI was found in 57 (46.3%) patients. Total duration of GC did not differ between those with and without AI (p = 0.711). Patients with GC induced AI had a significantly lower pre-synacthen baseline cortisol as compared to patients without AI. A cut off pre-synacthen baseline cortisol of ≥223.5 nmol/l had a specificity of 100% for identifying individuals without biochemical AI. Patients with GC induced AI took a mean of 8.7 ± 4.6 months (mean ± SD) to recover. Patients with persistent AI had a significantly lower index post-synacthen cortisol measurement. CONCLUSIONS: We demonstrate that biochemically proven GC induced AI is common in patients with glomerular diseases, is not predicted by daily dose or duration and takes a considerable time to recover. The study supports the use of morning basal cortisol testing as an appropriate means to avoid the need for SSTs in all patients and should be performed in all patients prior to consideration of GC withdrawal after 3 months duration.

8.
Autoimmun Rev ; 18(5): 535-541, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30844552

RESUMO

BACKGROUND: Consensus guidelines are not available for the use of immunoglobulin replacement therapy (IGRT) in patients developing iatrogenic secondary antibody deficiency following B-cell targeted therapy (BCTT) in autoimmune rheumatic disease. OBJECTIVES: To evaluate the role of IGRT to manage hypogammaglobulinemia following BCTT in autoimmune rheumatic disease (AIRD). METHODS: Using an agreed search string we performed a systematic literature search on Medline with Pubmed as vendor. We limited the search to English language papers with abstracts published over the last 10 years. Abstracts were screened for original data regarding hypogammaglobulinemia following BCTT and the use of IGRT for hypogammaglobulinemia following BCTT. We also searched current recommendations from national/international organisations including British Society for Rheumatology, UK Department of Health, American College of Rheumatology, and American Academy of Asthma, Allergy and Immunology. RESULTS: 222 abstracts were identified. Eight papers had original relevant data that met our search criteria. These studies were largely retrospective cohort studies with small patient numbers receiving IGRT. The literature highlights the induction of a sustained antibody deficiency, risk factors for hypogammaglobulinemia after BCTT including low baseline serum IgG levels, how to monitor patients for the development of hypogammaglobulinemia and the limited evidence available on intervention thresholds for commencing IGRT. CONCLUSION: The benefit of BCTT needs to be balanced against the risk of inducing a sustained secondary antibody deficiency. Consensus guidelines would be useful to enable appropriate assessment prior to and following BCTT in preventing and diagnosing hypogammaglobulinemia. Definitions for symptomatic hypogammaglobulinemia, intervention thresholds and treatment targets for IGRT, and its cost-effectiveness are required.


Assuntos
Antirreumáticos/efeitos adversos , Linfócitos B/imunologia , Imunoglobulinas/uso terapêutico , Síndromes de Imunodeficiência/induzido quimicamente , Síndromes de Imunodeficiência/terapia , Doenças Reumáticas/tratamento farmacológico , Agamaglobulinemia/induzido quimicamente , Agamaglobulinemia/terapia , Doenças Autoimunes/tratamento farmacológico , Humanos , Imunização Passiva/métodos , Estudos Retrospectivos , Rituximab/efeitos adversos
9.
BMC Nephrol ; 20(1): 58, 2019 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-30777023

RESUMO

BACKGROUND: Intravenous pulse methylprednisolone (MP) is commonly included in the management of severe ANCA associated vasculitis (AAV) despite limited evidence of benefit. We aimed to evaluate outcomes in patients who had, or had not received MP, along with standard therapy for remission induction in severe AAV. METHODS: We retrospectively studied 114 consecutive patients from five centres in Europe and the United States with a new diagnosis of severe AAV (creatinine > 500 µmol/L or dialysis dependency) and that received standard therapy (plasma exchange, cyclophosphamide and high-dose oral corticosteroids) for remission induction with or without pulse MP between 2000 and 2013. We evaluated survival, renal recovery, relapses, and adverse events over the first 12 months. RESULTS: Fifty-two patients received pulse MP in addition to standard therapy compared to 62 patients that did not. There was no difference in survival, renal recovery or relapses. Treatment with MP associated with higher risk of infection during the first 3 months (hazard ratio (HR) 2.7, 95%CI [1.4-5.3], p = 0.004) and higher incidence of diabetes (HR 6.33 [1.94-20.63], p = 0.002), after adjustment for confounding factors. CONCLUSIONS: The results of this study suggest that addition of pulse intravenous MP to standard therapy for remission induction in severe AAV may not confer clinical benefit and may be associated with more episodes of infection and higher incidence of diabetes.

11.
Ann Rheum Dis ; 78(3): 399-405, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30612116

RESUMO

OBJECTIVES: Cyclophosphamide induction regimens are effective for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but are associated with infections, malignancies and infertility. Mycophenolate mofetil (MMF) has shown high remission rates in small studies of AAV. METHODS: We conducted a randomised controlled trial to investigate whether MMF was non-inferior to cyclophosphamide for remission induction in AAV. 140 newly diagnosed patients were randomly assigned to MMF or pulsed cyclophosphamide. All patients received the same oral glucocorticoid regimen and were switched to azathioprine following remission. The primary endpoint was remission by 6 months requiring compliance with the tapering glucocorticoid regimen. Patients with an eGFR <15 mL/min were excluded from the study. RESULTS: At baseline, ANCA subtype, disease activity and organ involvement were similar between groups. Non-inferiority was demonstrated for the primary remission endpoint, which occurred in 47 patients (67%) in the MMF group and 43 patients (61%) in the cyclophosphamide group (risk difference 5.7%, 90% CI -7.5% to 19%). Following remission, more relapses occurred in the MMF group (23 patients, 33%) compared with the cyclophosphamide group (13 patients, 19%) (incidence rate ratio 1.97, 95% CI 0.96 to 4.23, p=0.049). In MPO-ANCA patients, relapses occurred in 12% of the cyclophosphamide group and 15% of the MMF group. In PR3-ANCA patients, relapses occurred in 24% of the cyclophosphamide group and 48% of the MMF group. Serious infections were similar between groups (26% MMF group, 17% cyclophosphamide group) (OR 1.67, 95% CI 0.68 to 4.19, p=0.3). CONCLUSION: MMF was non-inferior to cyclophosphamide for remission induction in AAV, but resulted in higher relapse rate. TRIAL REGISTRATION NUMBER: NCT00414128.

12.
Rheumatology (Oxford) ; 58(5): 889-896, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30590695

RESUMO

OBJECTIVES: The association of B cell targeted therapies with development of hypogammaglobulinaemia and infection is increasingly recognized. Our aim was to develop consensus recommendations for immunoglobulin replacement therapy for management of hypogammaglobulinaemia following B cell targeted therapies in autoimmune rheumatic diseases. METHODS: A modified Delphi exercise involved a 17-member Taskforce committee, consisting of immunologists, rheumatologists, nephrologists, haematologists, a gastroenterologist, an immunology specialist nurse and a patient representative. The first round identified the most pertinent topics to address in the recommendations. A search string was agreed upon for the identification of publications in PubMed focusing on these areas, for a systematic literature review. Original data was presented from this review to the Taskforce committee. Recommendations from the British Society for Rheumatology, the UK Department of Health, EULAR, the ACR, and the American Academy of Allergy, Asthma, and Immunology were also reviewed. The evidence was discussed in a face-to-face meeting to formulate recommendation statements. The levels of evidence and statements were graded according to Scottish Intercollegiate Guidelines Network methodology. RESULTS: Three overarching principles, eight recommendation statements and a research agenda were formulated. The Taskforce committee voted on these statements, achieving 82-100% agreement for each recommendation. The strength of the recommendations was restricted by the low quality of the available evidence, with no randomized controlled trial data. The recommendations cover risk factors, monitoring, referral for hypogammaglobulinaemia; indications, dosage and discontinuation of immunoglobulin replacement therapy. CONCLUSION: These are the first recommendations specifically formulated for B cell targeted therapies related to hypogammaglobulinaemia in autoimmune rheumatic diseases. The recommendations are to aid health-care professionals with clinical decision making for patients with hypogammaglobulinaemia.

13.
Best Pract Res Clin Rheumatol ; 32(1): 125-136, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-30526892

RESUMO

Survival following a diagnosis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) has improved since the introduction of cyclophosphamide-based immunosuppressive regimens and is now almost 80% at 5 years. However, mortality remains 2.6 times greater in the population with AAV than in an age- and sex-matched general population. The greatest risk of harm for patients with AAV is during the first year of diagnosis and from the adverse events associated with treatment rather than with active vasculitis. Infection, cardiovascular disease (CVD) and malignancy are the most common causes of death during follow-up. New regimens including rituximab, although with an efficacy similar to that of cyclophosphamide, have not yet shown a clear reduction in adverse events. Therapy for AAV must currently encompass a much greater focus on preventing harm from treatment through vaccination, Pneumocystis jirovecii pneumonia (PJP) prophylaxis, CVD risk assessment and bone protection measures.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Imunossupressores/uso terapêutico , Rituximab/uso terapêutico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Humanos , Imunossupressores/farmacologia , Rituximab/farmacologia , Resultado do Tratamento
14.
BMJ Open ; 8(10): e023769, 2018 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-30377212

RESUMO

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. TRIAL REGISTRATION NUMBER: ISRCTN11929227.

15.
Ann Rheum Dis ; 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30487151

RESUMO

BACKGROUND: IgA vasculitis (IgAV, Henoch-Schönlein purpura) is a small-vessel vasculitis most common in children but also occurring in adults. Case series have suggested that IgAV may be associated with cardiovascular disease and venous thromboembolism, but this has not been evaluated in population-based studies. Renal disease and hypertension are possible complications of the disease with unknown incidence. METHODS: Using a large UK primary care database, we conducted an open retrospective matched cohort study of cardiovascular, venous thrombotic and renal outcomes in adult-onset and childhood-onset IgAV. Control participants were selected at a 2:1 ratio, matched for age and sex. Adjusted HRs (aHRs) were calculated using Cox proportional hazards models. RESULTS: 2828 patients with adult-onset IgAV and 10 405 patients with childhood-onset IgAV were compared with age-matched and sex-matched controls. There was significantly increased risk of hypertension (adult-onset aHR 1.42, 95% CI 1.19 to 1.70, p < 0.001; childhood-onset aHR 1.52, 95% CI 1.22 to 1.89, p < 0.001) and stage G3-G5 chronic kidney disease (adult-onset aHR 1.54, 95% CI 1.23 to 1.93, p < 0.001; childhood-onset aHR 1.89, 95% CI 1.16 to 3.07, p=0.010). There was no evidence of association with ischaemic heart disease, cerebrovascular disease or venous thromboembolism. All-cause mortality was increased in the adult-onset IgAV cohort compared with controls (aHR 1.27, 95% CI 1.07 to 1.50, p=0.006). CONCLUSIONS: Patients with IgAV are at increased risk of hypertension and chronic kidney disease (CKD) compared with individuals without IgAV; analysis restricted to adult-onset IgAV patients showed increased mortality. Appropriate surveillance and risk factor modification could improve long-term outcomes in these patients.

16.
Artigo em Inglês | MEDLINE | ID: mdl-30358903

RESUMO

OBJECTIVE: Patients with chronic kidney disease (CKD) have dysregulated cortisol metabolism secondary to changes in 11ß-hydroxysteroid dehydrogenase (11ß-HSD) enzymes. The determinants of this and its clinical implications are poorly defined. METHODS: We performed a cross-sectional study to characterize shifts in cortisol metabolism in relation to renal function, inflammation and glycaemic control. Systemic activation of cortisol by 11ß-HSD was measured as the metabolite ratio (tetrahydrocortisol [THF]+5α-tetrahydrocortisol [5αTHF])/tetrahydrocortisone (THE) in urine. RESULTS: The cohort included 342 participants with a median age of 63 years, median estimated glomerular filtration rate (eGFR) of 28 mL/min/1.73 m2 and median urine albumin-creatinine ratio of 35.5 mg/mmol. (THF+5αTHF)/THE correlated negatively with eGFR (Spearman's ρ = -0.116, P = 0.032) and positively with C-reactive protein (ρ = 0.208, P < 0.001). In multivariable analysis, C-reactive protein remained a significant independent predictor of (THF+5αTHF)/THE, but eGFR did not. Elevated (THF+5αTHF)/THE was associated with HbA1c (ρ = 0.144, P = 0.008) and diabetes mellitus (odds ratio for high vs low tertile of (THF+5αTHF)/THE 2.57, 95% confidence interval 1.47-4.47). Associations with diabetes mellitus and with HbA1c among the diabetic subgroup were independent of eGFR, C-reactive protein, age, sex and ethnicity. CONCLUSIONS: In summary, glucocorticoid activation by 11ß-HSD in our cohort comprising a spectrum of renal function was associated with inflammation and impaired glucose control.

17.
J Infect Dis ; 2018 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-30102389

RESUMO

Background: Infection is the leading cause of death in ANCA-associated vasculitis (AAV). Expansion of CD4+CD28null T-cells is associated with increased risk of infection and mortality, but is only present in cytomegalovirus-seropositive individuals. We hypothesised that subclinical cytomegalovirus reactivation drives CD4+CD28null T-cell expansion; that this is associated with impaired immune response to heterologous antigens, and that anti-viral therapy may ameliorate this. Methods: In a proof-of-concept open-label clinical trial, 38 cytomegalovirus-seropositive AAV patients were randomised to receive valaciclovir for 6-months or no intervention. Cytomegalovirus reactivation was measured monthly in plasma and urine. CD4+CD28null T-cells were enumerated at baseline and at 6 months. At 6 months, 36 patients were vaccinated with a 13-valent pneumococcal vaccine. Serotype-specific IgG was assayed before and 4 weeks post-vaccination to calculate the antibody-response-ratio (ARR). Results: Valaciclovir treatment suppressed subclinical cytomegalovirus reactivation and reduced CD4+CD28null T-cell proportion. CD4+CD28null T-cell reduction correlated with improved vaccine response, whilst cytomegalovirus reactivation associated with reduced response to vaccination. Furthermore, expansion of CD4+CD28null T-cells was associated with a reduction in the functional capacity of the CD4 compartment. Conclusion: Suppression of cytomegalovirus may improve the immune response to a T-cell dependent pneumococcal vaccination in patients with AAV, thus offering potential clinical benefit. Trial registration identifier: NCT01633476.

18.
Arthritis Res Ther ; 20(1): 194, 2018 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-30157919

RESUMO

BACKGROUND: Cardiovascular 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. METHODS: CD4+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. RESULTS: CD4+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). CONCLUSION: The 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.

19.
PLoS One ; 13(4): e0195730, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29659606

RESUMO

Patients with chronic kidney disease (CKD) have an increased risk of infection and poorer responses to vaccination. This suggests that CKD patients have an impaired responsiveness to all antigens, even those first encountered before CKD onset. To examine this we evaluated antibody responses against two childhood vaccine antigens, tetanus (TT) and diphtheria toxoids (DT) and two common pathogens, cytomegalovirus (CMV) and Salmonella enterica serovar Enteritidis (SEn) in two independent cohorts consisting of age-matched individuals with and without CKD. Sera were evaluated for antigen-specific IgG titres and the functionality of antibody to SEn was assessed in a serum bactericidal assay. Surprisingly, patients with CKD and control subjects had comparable levels of IgG against TT and DT, suggesting preserved humoral memory responses to antigens encountered early in life. Lipopolysaccharide-specific IgG titres and serum bactericidal activity in patients with CKD were also not inferior to controls. CMV-specific IgG titres in seropositive CKD patients were similar or even increased compared to controls. Therefore, whilst responses to new vaccines in CKD are typically lower than expected, antibody responses to antigens commonly encountered prior to CKD onset are not. The immunodeficiency of CKD is likely characterised by failure to respond to new antigenic challenges and efforts to improve patient outcomes should be focussed here.


Assuntos
Antígenos/imunologia , Interações Hospedeiro-Patógeno/imunologia , Imunidade Humoral , Memória Imunológica , Infecção/etiologia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/imunologia , Idoso , Anticorpos Antibacterianos/imunologia , Biomarcadores , Feminino , Humanos , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/etiologia
20.
BMJ Open ; 8(1): e019630, 2018 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-29362273

RESUMO

OBJECTIVES: This study aimed to investigate the impact of research training funded via the National Health Service (NHS) on medical trainees compared with traditional clinical research training fellowships (CRTFs). DESIGN, SETTING AND PARTICIPANTS: Online survey of 221 clinical trainees who had completed a period of research during their clinical training between 2009 and 2015 in the West Midlands. MAIN OUTCOME MEASURES: Research outcomes. RESULTS: Overall response rate was 59%, of whom 72 participants were funded by CRTFs and 51 funded by the NHS. Although participants with CRTFs were more likely to be awarded a higher degree compared with those on NHS-administered funding (66/72 CRTFs and 37/51 NHS, P=0.005), similar proportions of NHS-funded and CRTF-funded participants entered clinical lecturer posts on completing initial research training (8/51 NHS and 16/72 CRTF, P=0.37). 77% of participants had three or more publications (CRTF 57 and NHS 39, P=0.72). 57 participants had completed clinical training; similar proportions of CRTF-funded and NHS-funded trainees had research included in their consultant contract (12/22 NHS and 14/26 CRTF, P=0.96) or were appointed to academic posts (3 of 25 NHS funded and 6 of 32 CRTF, P>0.05). 95% of participants would recommend to colleagues and 82% of participants felt the research experience improved their provision of clinical care with no difference between CRTF-funded and NHS-funded participants (P=0.49). Continuing to participate in clinical work during the research reduced reports of trainee difficulty on returning to clinical work (23/108 continued clinical work vs 12/22 no clinical work, P=0.001). CONCLUSION: Research training funded by the NHS provides a quality experience and contributes to the clinical academic capacity within the UK. More needs to be done to support NHS participants to successfully achieve a higher degree.


Assuntos
Bolsas de Estudo/economia , Organização do Financiamento , Pesquisa/economia , Medicina Estatal/economia , Estudos Transversais , Feminino , Humanos , Masculino , Pesquisa/educação , Estudos Retrospectivos , Inquéritos e Questionários
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