R A Stockley

University of Birmingham, Birmingham, England, United Kingdom

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Publications (248)1617.29 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory condition with a complex pathophysiology. In COPD, the immune response involves the adaptive immune system, although the antigenic stimulus driving this response is unknown. During the process of antibody synthesis an excess of free light chains (FLCs) are produced and secreted into the circulation. High polyclonal FLC concentrations have been found in several autoimmune and inflammatory conditions such as systemic lupus erythematosus and rheumatoid arthritis. Thus, FLCs are being investigated as a biomarker of immune activation, disease activity, and severity in these conditions. Our aim was to establish whether serum FLCs could be a marker of phenotypic variation or predict poor outcome in patients with usual and alpha-1-antitrypsin deficiency (A1ATD)-related COPD. Methods We measured FLC concentrations in 294 COPD patients with A1ATD-related and 85 patients with usual COPD using the Freelite serum FLC assay (The Binding Site Ltd, Birmingham, UK). We then compared combined (κ and λ) FLC (cFLC) concentrations in different subgroups defined by the presence of chronic bronchitis, colonisation of the lower respiratory tract, and subsequent mortality. In addition, we measured the estimated glomerular filtration rate (eGFR) of patients included in the study. Findings Our preliminary data showed that in A1ATD-related COPD and usual COPD, cFLC concentrations were significantly higher in patients with chronic bronchitis than in those without bronchitis (p=0·008 vs p=0·047). Patients with A1ATD-related COPD who were chronically colonised with pathogenic organisms in their stable state also had significantly higher cFLC concentrations than did those who were not colonised (p=0·036). A multiple regression analysis showed that eGFR and the presence of chronic bronchitis significantly predicted cFLC concentrations in patients with A1ATD: renal function was the strongest predictor (β=−0·326, p<0·0001) followed by the presence of chronic bronchitis (β=0·147, p=0·01). A similar trend was seen in the usual COPD group although this did not meet statistical significance (eGFR β=−0·220, p=0·055; chronic bronchitis β=0·224, p=0·061). The 33 A1ATD patients who subsequently died also had significantly higher cFLC concentrations (p=0·005) than did those still alive. Interpretation The higher cFLC concentrations in patients with A1ATD-related COPD who have chronic bronchitis and colonised lower respiratory tracts could mean that there is a greater adaptive immune response in these individuals. The drive behind this response might come directly from microorganisms or through self-perpetuating autoimmune events. Within the specialty of COPD clinical management, there is a move towards a more individualised approach to treating different clinical phenotypes. Measurement of serum FLCs might have a potential role as a biomarker to help stratify patients. The higher cFLC concentrations in patients with renal impairment is unsurprising in view of their renal clearance, but raised polyclonal FLCs have also been shown to be a predictor of mortality in the general population. Our mortality results suggest that FLCs could have a role in risk stratification for patients with COPD, but further investigation is needed. Funding Grifols Therapeutics.
    The Lancet 02/2014; 383:S28. DOI:10.1016/S0140-6736(14)60291-9 · 39.21 Impact Factor
  • Thorax 11/2013; 68(Suppl 3):A59-A60. DOI:10.1136/thoraxjnl-2013-204457.121 · 8.56 Impact Factor
  • H Stone, A Pye, R.A. Stockley
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    ABSTRACT: In addition to emphysema alpha-1-antitrypsin deficiency (AATD) has been shown to be associated with several inflammatory conditions, including bronchiectasis, vasculitis, (in particular Wegener's granulomatosis), and panniculitis, suggesting neutrophil proteinases also play a role in their pathophysiology. However, it remains unknown whether other inflammatory diseases are also more prevalent in AATD than the general population. The current study describes the prevalence of other co-morbidities in AATD with particular emphasis on inflammatory bowel disease. The case notes of 651 PiZZ or PiZnull patients attending the UK national centre for AATD between 1996 and 2011 were reviewed. The prevalence of inflammatory bowel disease (1.5%) was higher than that predicted in the UK (0.4%). Ten patients had a confirmed diagnosis of ulcerative colitis, and 1 had Crohn's disease. In 2 cases there was a family history of inflammatory bowel disease and all but 1 patient were ex or never smokers. There was also a higher prevalence of hypothyroidism in this patient group than expected for the UK population - 26 cases (7.2% of females and 1.3% of males). The current study of the UK cohort of patients with AATD confirmed a higher prevalence of ulcerative colitis than would be expected in the general population, providing further evidence of a potential link between these 2 conditions. In addition, the data suggested a potential link between hypothyroidism and AATD.
    Respiratory medicine 10/2013; 108(2). DOI:10.1016/j.rmed.2013.10.006 · 2.92 Impact Factor
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    ABSTRACT: Abstract Knowledge about the pathogenesis and pathophysiology of chronic obstructive pulmonary disease (COPD) has advanced dramatically over the last 30 years. Unfortunately, this has had little impact in terms of new treatments. Over the same time frame, only one new class of medication for COPD has been introduced. Even worse, the rate at which new treatments are being developed is slowing. The development of new tools for the assessment of new treatments has not kept pace with understanding of the disease. In part, this is because drug development tools require a regulatory review, and no interested party has been in a position to undertake such a process. In order to facilitate the development of novel tools to assess new treatments, the Food and Drug Administration, in collaboration with the COPD Foundation, the National Heart Lung and Blood Institute and scientists from the pharmaceutical industry and academia conducted a workshop to survey the available information that could contribute to new tools. Based on this, a collaborative project, the COPD Biomarkers Qualification Consortium, was initiated. The Consortium in now actively preparing integrated data sets from existing resources that can address the problem of drug development tools for COPD.
    COPD Journal of Chronic Obstructive Pulmonary Disease 06/2013; 10(3):367-377. DOI:10.3109/15412555.2012.752807 · 2.62 Impact Factor
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    ABSTRACT: Neutrophil elastase (NE) activity is increased in bronchiectasis and may play a role in this condition. We wished to determine the effect of AZD9668, a selective oral inhibitor of NE. Efficacy and safety of AZD9668 60 mg twice daily over 4 weeks were evaluated in a randomised, double-blind, placebo-controlled, parallel-group, Phase II, signal-searching study in patients with bronchiectasis. Outcome measures included: waking and post-waking sputum neutrophil counts; lung function tests; 24-h sputum weight; BronkoTest(®) diary card data; St George's Respiratory Questionnaire for COPD patients (SGRQ-C); sputum NE activity; inflammatory biomarker levels; desmosine levels; adverse events, safety haematology and biochemistry. AZD9668 levels in plasma and sputum were measured to confirm exposure. Thirty-eight patients were randomised: 16 to placebo and 22 to AZD9668. There was no change in sputum neutrophils with AZD9668. Forced expiratory volume in 1 s improved by 100 mL in the AZD9668 group compared with placebo (p = 0.006). Significant changes (defined a priori as p < 0.1) in favour of AZD9668 were also seen in slow vital capacity, plasma interleukin-8, and post-waking sputum interleukin-6 and Regulated on Activation, Normal T-cell Expressed and Secreted levels. Non-significant changes in favour of AZD9668 were seen in other lung function tests, sputum weight and the SGRQ-C. AZD9668 was well tolerated. In this small signal-searching study, 4 weeks' treatment with AZD9668 improved lung function in patients with bronchiectasis and there were trends for reductions in sputum inflammatory biomarkers. Larger studies of longer duration would be needed to confirm the potential benefits of this agent in bronchiectasis. Registration: NCT00769119.
    Respiratory medicine 02/2013; 107(4). DOI:10.1016/j.rmed.2012.12.009 · 2.92 Impact Factor
  • R A Stockley
    COPD Journal of Chronic Obstructive Pulmonary Disease 01/2013; DOI:10.3109/15412555.2013.758442 · 2.62 Impact Factor
  • N. J. Sinden, E. Sapey, G. M. Walton, R. A. Stockley
    Thorax 11/2012; 67:A41-A42. DOI:10.1136/thoraxjnl-2012-202678.091 · 8.56 Impact Factor
  • H. Stone, R. Edgar, R. Stockley
    Thorax 11/2012; 67(Suppl 2):A99-A99. DOI:10.1136/thoraxjnl-2012-202678.323 · 8.56 Impact Factor
  • American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California; 05/2012
  • H. Stone, A. Pye, R. A. Stockley
    Thorax 12/2011; 66(Suppl 4):A86-A86. DOI:10.1136/thoraxjnl-2011-201054c.45 · 8.56 Impact Factor
  • Thorax 12/2011; 66(Suppl 4):A38-A38. DOI:10.1136/thoraxjnl-2011-201054b.78 · 8.56 Impact Factor
  • Thorax 12/2011; 66(Suppl 4):A37-A37. DOI:10.1136/thoraxjnl-2011-201054b.76 · 8.56 Impact Factor
  • Thorax 12/2011; 66:A59-A59. DOI:10.1136/thoraxjnl-2011-201054b.129 · 8.56 Impact Factor
  • Deborah Whitters, Robert Stockley
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    ABSTRACT: Non-cystic fibrosis bronchiectasis is characterised by irreversibly dilated bronchi usually associated with chronic sputum production, bacterial colonisation of the lower respiratory tract, inflammation and frequent exacerbations. Irrespective of the underlying cause, this represents failure of the host defence to maintain sterility of the respiratory tract. To review the interactions and associations of non-cystic fibrosis bronchiectasis with the inate and adaptive immune systems with particular emphasis on known failure of local defences established deficiencies of the adaptive immune system. In addition we wished to explore potential subtle changes in the host defence which can lead to bacterial colonisation together with bacterial factors that aid colonisation of the lower respiratory tract and impair antibiotic response. This latter concept is considered with particular reference to Pseudomonas aeruginosa, which is often found in the airway secretions of patients with non-cystic fibrosis bronchiectasis and may act as a model for other organisms. An extensive literature review was undertaken to provide a comprehensive review of immunity and bacterial colonisation in non-cystic fibrosis bronchiectasis, with focus on in vitro studies examining bacterial factors which may facilitate colonisation together with potential implications for management. These themes provide a review of the current understanding of non-cystic fibrosis bronchiectasis together with areas for future research and potential therapeutic strategies.
    Thorax 09/2011; 67(11):1006-13. DOI:10.1136/thoraxjnl-2011-200206 · 8.56 Impact Factor
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    ABSTRACT: Small studies have linked α1 antitrypsin (α1AT) deficiency to patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). To test the validity and the mechanism of this association between α1AT and AAV. 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. 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. 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.
    Annals of the rheumatic diseases 08/2011; 70(10):1851-6. DOI:10.1136/ard.2011.153569 · 9.27 Impact Factor
  • Jennie Gane, Robert Stockley
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    ABSTRACT: Chronic obstructive pulmonary disease (COPD) is a common and important disease. Neutrophils have been shown to play a fundamental role in its development and progression. Understanding the mechanisms underlying the trafficking of neutrophils across the vascular endothelium into the lung could potentially allow the development of targeted biological treatments. The early stages of neutrophil tethering, adherence to and rolling on the endothelium have been determined. The later stages of diapedesis through the glycocalyx, endothelial cell (EC) layer and basement membrane, which are less well characterised, have been reviewed here. Evidence obtained from in vitro and in vivo work, concerning the implicated adhesion molecules on the neutrophil and endothelium, the mechanisms for neutrophil navigation through the EC junction (paracellular route) and evidence for transmigration through the body of an EC itself (transcellular route), is considered. The mechanisms are complex and are often disease and stimulus specific. There is evidence that a significant degree of redundancy occurs. Transmigration in the lung differs from that in other organs in that the neutrophil can exit the circulation either through the postcapillary venule in the systemic circulation or through the capillary in the pulmonary circulation. A number of factors make the mechanisms of transmigration within the lung and COPD model unique. These include physical differences between the flow through the capillary and the postcapillary venule, the modulating effect of the alveolar epithelium and other cells such as the macrophage, the presence of a 'diseased' neutrophil and indeed the presence or absence of acute, acute on chronic or chronic pulmonary disease.
    Thorax 05/2011; 67(6):553-61. DOI:10.1136/thoraxjnl-2011-200088 · 8.56 Impact Factor
  • American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado; 05/2011
  • American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado; 05/2011
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    ABSTRACT: Vitamin D-binding protein (DBP) genetic polymorphisms have been associated with chronic obstructive pulmonary disease (COPD). DBP has an indirect role in macrophage activation; thus it was hypothesised that DBP is present in the airway and contributes to lung disease by this mechanism. 471 PiZZ subjects with α1-antitrypsin deficiency (AATD) were genotyped for tag single nucleotide polymorphisms (SNPs) covering the DBP gene (GC), together with known functional variants, prior to seeking association with COPD phenotypes. 140 subjects with usual COPD and 480 controls were available for replication. Vitamin D and DBP levels were measured by tandem mass spectrometry and ELISA, respectively, in serum and DBP in the sol phase of sputum in a subset of 60 patients. Concentrations were related to phenotype and to alveolar macrophage activation. rs2070741 was associated with airway bacterial colonisation (p=0.04) and bronchiectasis (p=0.01), as was rs7041 (p=0.03) which also influenced vitamin D concentrations (p=0.01). The GC2 variant predisposed to bronchiectasis in AATD (p=0.04) and protected against COPD (p=0.05); the latter association was replicated in usual COPD versus controls (p=0.04). Circulating DBP related inversely to forced expiratory volume in 1 s (FEV(1)) (p=0.02), in direct contrast to vitamin D, where deficiency related to low FEV(1) (p=0.04). Sol DBP related directly to alveolar macrophage activation (p=0.004). The genetic association of DBP with COPD may be mediated by effects on macrophage activation, since DBP relates to FEV(1), and affects macrophage activation. Vitamin D effects may be independent of this, relating more strongly to innate immunity.
    Thorax 03/2011; 66(3):205-10. DOI:10.1136/thx.2010.140921 · 8.56 Impact Factor
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    ABSTRACT: Liberation of elastin peptides from damaged lung may be a mechanism of autoimmune lung disease. Citrullination, and anti-citrullinated protein antibody formation occurs in smokers, but the role of smoking in autoantibody generation relevant to pulmonary disease is unclear. Anti-elastin, anti-cyclic citrullinated peptide (anti-CCP) and anti-mutated citrullinated vimentin (anti-MCV) antibodies were measured in 257 subjects with α₁-antitrypsin deficiency (AATD), 113 subjects with usual chronic obstructive pulmonary disease (COPD) and 22 healthy nonsmokers. Levels were compared between groups, against phenotypic features and against smoke exposure. Anti-elastin antibodies were higher in controls relative to AATD (p = 0.008) and usual COPD (p < 0.00001), and in AATD relative to usual COPD (p < 0.00001). Anti-elastin levels showed a threshold at 10 pack-yrs, being higher in those who had smoked less (p = 0.004). No relationships between antibody levels and clinical phenotype were seen after adjustment for smoke exposure. Anti-CCP antibodies were higher in usual COPD than AATD (p = 0.002) but the relationship to smoke exposure was less clear. Smoke exposure is the main determinant of anti-elastin antibody levels, which fall after 10 pack-yrs. Local antibody complexes may be a better measure of elastin directed autoimmunity than circulating levels.
    European Respiratory Journal 01/2011; 37(1):32-8. DOI:10.1183/09031936.00033710 · 7.13 Impact Factor

Publication Stats

6k Citations
1,617.29 Total Impact Points

Institutions

  • 1978–2014
    • University of Birmingham
      • • School of Clinical and Experimental Medicine
      • • School of Immunity and Infection
      Birmingham, England, United Kingdom
  • 1987–2013
    • Queen Elizabeth Hospital Birmingham
      Birmingham, England, United Kingdom
    • The Royal Orthopaedic Hospital NHS Foundation Trust
      Birmingham, England, United Kingdom
  • 2000–2012
    • The Queen Elizabeth Hospital
      • Department of Respiratory Medicine
      Tarndarnya, South Australia, Australia
  • 1990–2011
    • University Hospitals Birmingham NHS Foundation Trust
      • Department of Respiratory Medicine
      Birmingham, England, United Kingdom
    • Barnes Jewish Hospital
      San Luis, Missouri, United States
  • 2010
    • Leiden University Medical Centre
      Leyden, South Holland, Netherlands
  • 1985–2006
    • Leiden University
      Leyden, South Holland, Netherlands
  • 2002
    • Policlinico San Matteo Pavia Fondazione IRCCS
      Ticinum, Lombardy, Italy
    • Royal United Hospital Bath NHS Trust
      Bath, England, United Kingdom
  • 1995
    • Papworth Hospital NHS Foundation Trust
      Papworth, England, United Kingdom
  • 1994
    • University of Queensland
      • Department of Medicine
      Brisbane, Queensland, Australia
    • University of Cambridge
      • Department of Haematology
      Cambridge, England, United Kingdom