Cytomegalovirus infection is a risk factor for venous thromboembolism in ANCA-associated vasculitis.

BACKGROUND: Venous thromboembolism (VTE) is a common complication in patients with anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) and confers significant morbidity and mortality. Both acute and past cytomegalovirus (CMV) infection have been identified as risk factors for VTE in immunocompetent and immunosuppressed individuals. Here, we examine whether past exposure to CMV is a risk factor for VTE amongst patients with AAV. METHODS: We retrospectively analysed outcomes of patients with a new diagnosis of AAV from a UK cohort. All confirmed cases of VTE where CMV IgG serology was available were recorded. Retrospective collection of the same data for patients at a North American centre was used as a validation cohort. RESULTS: VTE was common with 12% of patients from the study cohort (total 259 patients) developing an event during the median follow-up period of 8.5 years of which 60% occurred within the first 12 months following diagnosis. Sixteen percent of CMV seropositive patients developed a VTE compared with 5% of patients who were seronegative (p = 0.007) and CMV seropositivity remained an independent predictor of VTE in multivariable analysis (HR 2.96 [1.094-8.011] p = 0.033). CMV seropositivity at diagnosis was confirmed as a significant risk factor for VTE in the American validation cohort (p = 0.032). CONCLUSIONS: VTE is common in patients with AAV, especially within the first year of diagnosis. Past infection with CMV is an independent risk factor associated with VTE in AAV.

Comparison of outcomes using the rituximab originator MabThera with the biosimilar Truxima in patients with ANCA-associated vasculitis.

OBJECTIVES: The use of rituximab (MabThera®), an anti-CD20 monoclonal antibody, is the most significant development in the management of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) since the introduction of cytotoxic therapy in 1950. Truxima® is the first anti-CD20 biosimilar approved for the same indications, and has been available in the UK since 2017. Significant cost savings have been reported when switching to biosimilars, which could lead to greater patient access to such treatment. Therefore, it is important to know whether patients' clinical and laboratory parameters respond equally well to biosimilars as to reference medicines, tested in clinical trials. METHOD: We retrospectively reviewed the clinical outcomes and laboratory parameters in 257 consecutive patients treated with anti-CD20 depletion therapy using MabThera or Truxima, for induction and maintenance of remission, in two tertiary renal centres between 2010 and 2019. RESULTS: We demonstrated no difference between patients treated with MabThera or Truxima in rates of remission, relapse, and hospitalization with infection when used for either induction or maintenance of remission of AAV. In one hospital subgroup analysis, we showed comparable levels of hypogammaglobulinaemia, B-cell depletion, and frequency of infusion reactions, with no significant differences. CONCLUSION: The efficacy and safety of the rituximab biosimilar Truxima are not inferior to the originator MabThera in patients with AAV. Truxima represents a cheaper and safe therapeutic alternative that could increase patient access to rituximab.

High-fat diet disrupts metabolism in two generations of rats in a parent-of-origin specific manner.

Experimental and epidemiological evidence demonstrate that ancestral diet might contribute towards offspring health. This suggests that nutrition may be able to modify genetic or epigenetic information carried by germ cells (GCs). To examine if a parental high fat diet (HFD) influences metabolic health in two generations of offspring, GC-eGFP Sprague Dawley rats were weaned onto HFD (45% fat) or Control Diet (CD; 10% fat). At 19 weeks, founders (F0) were bred with controls, establishing the F1 generation. HFD resulted in 9.7% and 14.7% increased weight gain in male and female F0 respectively. F1 offspring of HFD mothers and F1 daughters of HFD-fed fathers had increased weight gain compared to controls. F1 rats were bred with controls at 19 weeks to generate F2 offspring. F2 male offspring derived from HFD-fed maternal grandfathers exhibited increased adiposity, plasma leptin and luteinising hormone to testosterone ratio. Despite transmission via the founding male germline, we did not find significant changes in the F0 intra-testicular GC transcriptome. Thus, HFD consumption by maternal grandfathers results in a disrupted metabolic and reproductive hormone phenotype in grandsons in the absence of detectable changes in the intra-testicular GC transcriptome.

Can we identify patients with different illness schema following an acute exacerbation of COPD: a cluster analysis.

INTRODUCTION: Pulmonary Rehabilitation (PR) reduces hospital admissions following an acute exacerbation of Chronic Obstructive Pulmonary Disease (COPD) but adherence is known to be poor. Patients' illness perceptions may affect adherence to disease-management strategies but to date have not been explored following an exacerbation. The study aim is two-fold; firstly to prospectively explore acceptance and uptake of post-exacerbation PR and secondly to identify possible clusters of patients' illness perceptions following hospitalisation for an exacerbation of COPD. METHODS: Patients admitted to hospital with an exacerbation of COPD were recruited to a prospective observational study. Self-reported illness perceptions, mood, health status and self-efficacy were assessed. Acceptance and uptake of PR were recorded at six months. Cluster analysis of Illness Perceptions Questionnaire-Revised data was used to establish groups of patients holding distinct beliefs. RESULTS: 128 patients were recruited. Acceptance and uptake of PR following an acute exacerbation was poor with only 9% (n = 11) completing the programme. Cluster analysis revealed three distinct groups: Cluster 1 'in control' (n = 52), Cluster 2 'disengaged' (n = 36) and Cluster 3 'distressed' (n = 40). Significant between-cluster differences were observed in mood, health status and self-efficacy (p < 0.01). Acceptance and uptake of PR did not differ between clusters. CONCLUSIONS: Acceptance/uptake of post-exacerbation PR was found to be poor. Three distinct illness schema exist in patients following an acute exacerbation. This information may be useful in developing novel psychologically-informed interventions designed to reduce feelings of distress and perhaps facilitate a PR intervention for this vulnerable population.

Have we underestimated the efficacy of pulmonary rehabilitation in improving mood?

BACKGROUND: Patients with COPD have a high prevalence of anxiety and depression. The efficacy of pulmonary rehabilitation (PR) in treating more severe anxiety and depression is unknown. The study aimed to explore the effectiveness of PR in reducing symptoms of anxiety and depression across a spectrum of severities. METHODS: The study used principles of comparative effectiveness research. Data was analysed from 518 patients with COPD [57.5% male, mean (SD) age 69.2 years (± 8.8 years)]. Patients were categorised into 3 groups based on their hospital anxiety and depression scale (HADS) scores pre PR ('none' 0-7, 'probable' 8-10 and 'presence' 11-21). A responder was defined as achieving a change of ≥ 48 m on the incremental shuttle walk test (ISWT). Patients were categorised as 'completers' if they attended their discharge assessment for PR. RESULTS: Anxiety and depression did not reduce following PR in patients with no symptoms (p > 0.05). Patients with a 'probable' or 'presence' of symptoms had significant reductions (both p < 0.001). There was a difference between sub-groups in change for anxiety and depression with patients scoring highest on the HADS having the greatest reductions (p < 0.001). There was no correlation between anxiety or depression and completion of PR (p > 0.05). Responders and non-responders did not differ in their anxiety or depression levels (p > 0.05). CONCLUSION: PR is effective in reducing symptoms of anxiety and depression. Previous studies may have underestimated the effectiveness of the PR programme in improving mood.

ANCA-associated vasculitis is linked to carriage of the Z allele of α1 antitrypsin and its polymers.

BACKGROUND: Small studies have linked α1 antitrypsin (α1AT) deficiency to patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). OBJECTIVE: To test the validity and the mechanism of this association between α1AT and AAV. METHODS: The distribution of α1AT deficiency alleles Z and S was compared between 856 White Europeans with AAV and 1505 geographic and ethnically matched healthy controls. Genotyping was performed by allelic discrimination assay. RESULTS: were compared between cases and controls using χ(2) tests. The serum and renal biopsies for α1AT polymers were compared using the polymer-specific 2C1 antibody. The role of α1AT polymers in promoting inflammation was investigated by examining their ability to prime neutrophils for ANCA activation as assessed by CD62L shedding, superoxide production and myeloperoxidase degranulation. Results The Z but not the S allele was over-represented in the patients compared with controls (HR=2.25, 95% CI 1.60 to 3.19). Higher concentrations of polymers of α1AT were detected in serum from patients carrying the Z allele than in those not carrying the Z allele (median (IQR) 1.40 (0.91-3.32) mg/dl vs 0.17 (0.06-0.28) mg/dl, p<0.001); polymers of α1AT were also seen in the renal biopsy of a patient with vasculitic glomerulonephritis. Polymers of α1AT primed neutrophils with CD62L shedding and increased superoxide production following ANCA activation. Carriage of the Z allele was not associated with disease severity, survival or relapse. CONCLUSIONS: The Z but not the S deficiency allele is associated with AAV. Polymers of α1AT are present in the serum and glomeruli of at least some patients with the Z allele, which may promote inflammation through priming of neutrophils.

ANCA-stimulated neutrophils release BLyS and promote B cell survival: a clinically relevant cellular process.

OBJECTIVES: To determine a role for antineutrophil cytoplasmic antibody (ANCA)-activated neutrophils in promoting B cell survival through the release of B lymphocyte stimulator (BLyS). METHODS: Neutrophil BLyS expression was measured by flow cytometry. Concentrations of BLyS in cell supernatants and donor serum samples were measured by ELISA. Cell survival assays were carried out using an L3055 cell line and viability measured by flow cytometry. RESULTS: Tumour necrosis factor α and formyl-Met-Leu-Phe (fMLP) treatment of non-primed neutrophils and treatment of primed neutrophils with anti-PR3 ANCA IgG resulted in a significant increase in surface expression of BLyS within 30 min which returned to basal levels by 2 h. Supernatants from ANCA-stimulated neutrophils were shown to contain increased levels of BLyS and to promote the survival of the centroblast cell line L3055. Serum BLyS concentrations are increased in patients with active ANCA-associated systemic vasculitis and these levels are increased further following 1-3 months of treatment with rituximab. CONCLUSIONS: ANCA specifically causes the release of BLyS from activated neutrophils which can support B cell survival in vitro. The presence of serum BLyS in active disease and its increase following B cell depletion suggest it is an important factor in disease pathogenesis and may facilitate disease relapse.

Generic, symptom based, exercise rehabilitation; integrating patients with COPD and heart failure.

BACKGROUND: Patients with Chronic Heart Failure (CHF) develop similar symptoms of exertional breathlessness and fatigue as patients with COPD. Although pulmonary (exercise based) rehabilitation (PR) is an integral part of the management of COPD, the potential for exercise rehabilitation (ER) to assist patients with CHF may not be as readily appreciated. We investigated whether combined ER for patients with CHF and COPD was feasible and effective using the model of PR. METHODS: 57 patients with CHF were randomized 2:1 to 7 weeks ER (CHF-ER) or 7 weeks of usual care (CHF-UC). As a comparator 55 patients with COPD were simultaneously recruited to the same ER program (COPD-ER). The primary outcome measure was the Incremental Shuttle Walk Test (ISWT) and the secondary outcome measures were the Endurance Shuttle Walk Test (ESWT), isometric quadriceps strength and health status. RESULTS: 27 CHF and 44 COPD patients completed ER and 17 patients with CHF completed UC. The CHF-ER group made significant improvements, compared to CHF-UC, in the mean (95%CI) ISWT distance; 62(35-89)m vs -6(-11 to 33)m p < 0.001. The CHF-ER group also made statistically significant improvements in health status. The improvements in exercise performance and health status were similar between patients with CHF and COPD, treated with ER. CONCLUSION: Patients with CHF who undergo ER improve similarly in their exercise performance and health status to COPD. Combined training programs for COPD and CHF are effective and feasible, such that service provision could be targeted around common disability rather than the primary organ disease.

Plasma ammonia response to incremental cycling and walking tests in COPD.

OBJECTIVE: It is well documented that plasma ammonia accumulates during exercise under conditions of metabolic stress. Metabolic stress (when skeletal muscle ATP supply fails to meet demand) occurs at low work rates during cycling in patients with COPD, but not been described during walking. Walking is an important activity for many patients with COPD and is commonly prescribed in pragmatic outpatient pulmonary rehabilitation programmes. In this study we explored whether metabolic stress occurs during incremental walking at the low work rates these patients achieve. METHODS: Twenty-nine subjects with stable COPD [mean(SD) age 68(7)years, FEV(1) 50(19)% predicted] performed maximal cardiopulmonary exercise tests on a cycle ergometer and treadmill. Plasma ammonia concentration was measured at rest, 1 and 2min of exercise, peak exercise and 2min recovery. RESULTS: Subjects achieved mean(SD) cycle work rate of 57(20)W with VO(2max) 15.5(4.6)ml/min per kg, and treadmill distance 284(175)m with VO(2peak) 16.8(4.2)ml/min per kg. Plasma ammonia concentration rose significantly (p<0.001) with walking [mean(SEM) change 24.7(3.8)micromol/l] and cycling [mean(SEM) change 35.2(4.3)micromol/l], but peak exercise ammonia was lower in walking (p<0.01). In a subgroup of subjects (n=7) plasma ammonia did not rise during either cycling or walking despite similar lactate rise and peak exercise indices. CONCLUSION: Our data indicate that failure of muscle ATP re-synthesis to meet demand and development of metabolic stress can occur during walking in COPD patients at the low work rates these patients achieve. This may therefore be a factor contributing to exercise limitation independent of ventilatory limitation.

Pulmonary rehabilitation is successful for COPD irrespective of MRC dyspnoea grade.

BACKGROUND: It is not clear whether the benefits of pulmonary rehabilitation (PR) apply equally to patients with Chronic Obstructive Pulmonary Disease (COPD) with different levels of starting disability. We have therefore investigated the effect of pulmonary rehabilitation stratified by the MRC dyspnoea scale in patients with COPD. METHODS: This is a retrospective, observational study of data collected from 450 consecutive patients with COPD attending outpatient PR: 247 male, mean (SD) age 69.5 (8.9) yrs and FEV(1) 44.6 (19.7)% predicted. The Incremental Shuttle Walk Test (ISWT) was performed before and after the seven-week course RESULTS: 395 patients (88%) completed the programme. The mean (SD) baseline ISWT performance was 167 (113)m. The distribution of baseline MRC grades was 2 - 15.4%, 3 - 24.9%, 4 - 27.3% and 5 - 32.4%. The mean (95% CI) improvement in ISWT after PR for each MRC scale grade was highly significant (p<0.0005); 2 - 66 (50-83)m, 3 - 63 (50-75)m, 4 - 59 (49-70)m, and 5 - 54 (43-64)m. CONCLUSIONS: Patients with COPD, of all MRC dyspnoea grades, benefit comparably from pulmonary rehabilitation achieving both statistically and clinically meaningful improvements in exercise performance. MRC grade should therefore not be used to exclude patients from pulmonary rehabilitation.

Developing concepts in the pulmonary rehabilitation of COPD.

Randomised trials have demonstrated that pulmonary rehabilitation (PR) can improve dyspnoea, exercise tolerance and health related quality of life. Rehabilitation has traditionally been provided in secondary care to patients with moderate to severe disease. Current concepts are however recommending that it should be delivered in a primary and community care setting for patients with milder disease. There are several opportunities for spreading the word for PR in primary care. One of these is to improve access to PR for all those disabled by their disease by the increase of community schemes and one such scheme being utilised in Canada is reviewed. The essential components of PR include behavior change, patient self-management and prescriptive exercise. In the last decade new strategies have been developed to enhance the effects of exercise training. An overview of these new approaches being an adjunct to exercise training is reviewed. Although the role of exercise training is well established, we are only just beginning to appreciate the importance of behavior change and patient self-management in contributing to improved health and diminished healthcare resource utilisation.

Detecting oxygen desaturation in patients with COPD: incremental versus endurance shuttle walking.

BACKGROUND: There has been no direct comparison between an incremental and endurance walking test to detect the relative oxygen desaturation in patients with chronic obstructive pulmonary disease (COPD). This is of some importance as current guidelines have suggested that ambulatory oxygen should only be prescribed after a standard assessment and desaturation documented. No clear advice about the nature of the required exercise task is given. This study therefore compared the relative desaturation between the incremental shuttle walking test (ISWT) and the constant speed walking test (ESWT) and response to ambulatory oxygen. METHODS: Forty-one patients (29 male), mean (SD), age 71.18 (7.48) yrs, FEV(1) 0.85 (0.29) l with stable COPD were recruited after completion of a 7-week pulmonary rehabilitation programme. Patients completed a baseline (without carrying a cylinder) ISWT and ESWT and then, in random order in double blind fashion, completed the walk tests with a cylinder of air or a cylinder of oxygen. Measurements included distance walked, oxygen saturation, heart rate, perceived breathlessness and exertion (Borg scale). RESULTS: All patients desaturated (<4% below 90%). There was no significant difference in desaturation between the ISWT and the ESWT. There was a significant improvement in performance with supplementary oxygen compared to cylinder air (p<0.05) for both tests. However, compared to the baseline walk, supplementary oxygen did not enhance the distance walked for either test. There was a significant decrease in walking performance on both the ISWT and the ESWT when carrying an air cylinder compared with the control walk. When comparing the percentage difference between oxygen and air for responders (i.e. those that achieve a 10% or more increase), the ESWT showed a greater percentage change 42.1% compared to 26.1% for the ISWT. CONCLUSIONS: This study identifies that incremental and endurance walking provokes significant desaturation and that there is a short-term benefit of oxygen versus air in enhancing exercise performance. There was no significant difference in the level of desaturation between tests. Therefore the ISWT is a suitable exercise test that can be used to evaluate desaturation and is practically more realistic.

Minimum clinically important improvement for the incremental shuttle walking test.

BACKGROUND: The incremental shuttle walking test (ISWT) is used to assess exercise capacity in patients with chronic obstructive pulmonary disease (COPD) and is employed as an outcome measure for pulmonary rehabilitation. This study was designed to establish the minimum clinically important difference for the ISWT. METHODS: 372 patients (205 men) performed an ISWT before and after a 7-week outpatient pulmonary rehabilitation programme. After completing the course, subjects were asked to identify, from a 5-point Likert scale, the perceived change in their exercise performance immediately upon completion of the ISWT. The scale ranged from "better" to "worse". RESULTS: The mean (SD) age was 69.4 (8.4) years, forced expiratory volume in 1 s (FEV(1)) 1.06 (0.53) l and FEV(1)/forced vital capacity (FVC) ratio 50.8 (18.1)%. The baseline shuttle walking test distance was 168.5 (114.6) m which increased to 234.7 (125.3) m after rehabilitation (mean difference 65.9 m (95% CI 58.9 to 72.9)). In subjects who felt their exercise tolerance was "slightly better" the mean improvement was 47.5 m (95% CI 38.6 to 56.5) compared with 78.7 m (95% CI 70.5 to 86.9) in those who reported that their exercise tolerance was "better" and 18.0 m (95% CI 4.5 to 31.5) in those who felt their exercise tolerance was "about the same". CONCLUSION: Two levels of improvement were identified. The minimum clinically important improvement for the ISWT is 47.5 m. In addition, patients were able to distinguish an additional benefit at 78.7 m.

The plasma ammonia response to cycle exercise in COPD.

The plasma ammonia response to exercise in chronic obstructive pulmonary disease (COPD) was examined and the relationship between plasma ammonia concentration and muscle adenine nucleotide metabolism was explored. In total, 25 stable COPD patients and 13 similar-aged controls underwent incremental and constant-work rate cycle exercise tests. Arterialised venous blood was sampled at rest, at 1-min intervals during exercise and

IL-18 is upregulated in the kidney and primes neutrophil responsiveness in ANCA-associated vasculitis.

In antineutrophil cytoplasm autoantibody (ANCA)-associated systemic vasculitis (ASV), autoantibody-induced neutrophil activation is believed to cause organ damage. In vitro, tumor necrosis factor alpha (TNFalpha) primes neutrophils for ANCA stimulation and TNFalpha blockade has been successfully used to treat ASV. Nonetheless, irreversible organ damage can still occur, suggesting that other cytokines may circumvent TNFalpha blockade. We report that interleukin (IL)-18 deposition, as assessed by immunoperoxidase staining, is increased in renal biopsies from ASV patients. Immunofluorescence microscopy demonstrated that podocytes are the predominant glomerular IL-18-positive cell type, whereas in the interstitium, myofibroblasts, distal tubular epithelium, and infiltrating macrophages stained for IL-18. In vitro, IL-18 primed superoxide production by ANCA-activated neutrophils comparably to TNFalpha. IL-18-primed, ANCA-induced superoxide production was unaffected by anti-TNFalpha antibody, which abrogated TNFalpha priming. Furthermore, TNFalpha and IL-18 phosphorylated neutrophil p38 mitogen-activated protein kinase (MAPK), but IL-18-mediated p38 MAPK phosphorylation was unaffected by anti-TNFalpha antibody. The p38 MAPK inhibitor, SB20358, reduced IL-18-primed, ANCA-induced superoxide production in a concentration-dependent manner. ANCA-induced superoxide release was also sensitive to the Leukotriene B4 (LTB4) inhibitor MK-886. IL-18 priming was not associated with increased ANCA antigen expression on isolated neutrophils. We conclude that IL-18 is likely to be important for neutrophil recruitment and priming in ASV. Therapies targeting single priming agents may have limited efficacy in controlling disease.