Journal Club

Abstract

Systemic Steroid Exposure is Associated with Differential Methylation in Chronic Obstructive Pulmonary Disease. E.S. Wan, W. Qiu, A. Baccarelli, V.J. Carey, H. Bacherman, S.I. Rennard, A. Agusti, W.H. Anderson, D.A. Lomas, D.L. Demeo. Am J Respir Crit Care Med. 2012 Oct 11. [Epub ahead of print].

RATIONALE: Systemic glucocorticoids are used therapeutically to treat a variety of medical conditions. Epigenetic processes such as DNA methylation may reflect exposure to and may be involved in mediating the responses and side effects associated with these medications.

OBJECTIVE: To test the hypothesis that differences in DNA methylation are associated with current systemic steroid use.

METHODS: We obtained DNA methylation data at 27,578 CpG sites in 14,475 genes throughout the genome in two large, independent cohorts: the International COPD Genetics Network (ndiscovery = 1085) and the Boston Early Onset COPD study (nreplication = 369). Sites were tested for association with current systemic steroid use using generalized linear mixed models.

MAIN RESULTS: 511 sites demonstrated significant differential methylation by systemic corticosteroid use in all 3 of our primary models. Pyrosequencing validation confirmed robust differential methylation at CpG sites annotated to genes such as SLC22A18, LRP3, HIPK3, SCNN1A, FXYD1, IRF7, AZU1, SIT1, GPR97, ABHD16B, and RABGEF1. Functional annotation clustering demonstrated significant enrichment in intrinsic membrane components, hemostasis and coagulation, cellular ion homeostasis, leukocyte and lymphocyte activation and chemotaxis, protein transport, and responses to nutrients.

CONCLUSIONS: Our analyses suggest systemic steroid use is associated with site-specific differential methylation throughout the genome. Differentially methylated CpG sites were found in both biologically plausible and previously unsuspected pathways; these genes and pathways may be relevant in the development of novel targeted therapies.

Comments: For many COPD patients oral steroids seem to be more effective than inhaled steroids even at very low doses. The reasons for this are likely multifactorial but may include systemic steroids having effects on certain extrapulmonary manifestations of COPD that nonetheless effect their symptoms and propensity for exacerbations. The ability of this research to identify potential systemic therapeutic targets that may provide benefits without the adverse consequences of long term systemic steroids would be a significant advance.

The Effect of Emphysema on Computed Tomographic Measures of Airway Dimensions in Smokers. A.A. Diaz, M.K. Han, C.E. Come, R.S. Estepar, J.C. Ross, V. Kim, M.T. Dransfield, D. Curran-Everett, J.D. Schroeder, D.A. Lynch, J. Tschirren, E.K. Silverman, G.R. Washko. Chest. 2012 Oct 8. [Epub ahead of print]

BACKGROUND: In CT scans of smokers with COPD, the subsegmental airway wall area percent (WA%) is greater and more strongly correlated with FEV1% predicted than WA% obtained in the segmental airways. Since emphysema is linked to loss of airway tethering and may limit airway expansion, increases in WA% may be related to emphysema and not solely due to remodeling. We aimed to first determine if the stronger association of subsegmental vs. segmental WA% with FEV1% predicted is mitigated by emphysema; and second, to assess the relationships between emphysema, WA%, and total bronchial area (TBA).

METHODS: We analyzed CT segmental and subsegmental WA% (WA% = 100*wall area/TBA) of six bronchial paths and corresponding lobar emphysema, lung function, and clinical data in 983 smokers with COPD.

RESULTS: Compared to segmental, the subsegmental WA% had a greater effect on FEV1% predicted (–0.8 to –1.7% vs. –1.9 to –2.6% per 1-unit increase in WA%, respectively; P<0.05 for most bronchial paths). After adjusting for emphysema, the association between subsegmental WA% and FEV1% predicted was weakened in two bronchial paths. Increases in WA% between bronchial segments correlated directly with emphysema in all bronchial paths (P<0.05). In multivariate regression models, emphysema was directly related to subsegmental WA% in most bronchial paths and inversely related to subsegmental TBA in all bronchial paths.

CONCLUSION: The greater effect of subsegmental WA% on airflow obstruction is mitigated by emphysema. Part of the emphysema effect might be due to loss of airway tethering leading to reduction in TBA and increase in WA%.

Comments: Several studies have identified the central role of small airway damage in the pathophysiology of COPD. The role of alveolar destruction from emphysema and loss of smaller airway tethering has been proposed in past and is supported by this study. While it is typically proposed that only 20–30% of COPD patients have significant emphysema it is possible that we underestimate the presence of emphysema in patients typically considered to be purely chronic bronchitis that do not have CT performed. It is possible also that CT scan may underestimate emphysematous changes that may be only appreciated on direct tissue examination. Further studies are needed to elucidate the importance of these findings.

Chronic obstructive pulmonary disease as a cardiovascular risk factor. Results of a case-control study (CONSISTE study). P. de Lucas-Ramos, J.L. Izquierdo-Alonso, J.M. Moro, J.F. Frances, P.V. Lozano, J.M. Bellon-Cano; CONSISTE study group. Int J Chron Obstruct Pulmon Dis. 2012;7:679-86. Epub 2012 Oct 1.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) patients present a high prevalence of cardiovascular disease. This excess of comorbidity could be related to a common pathogenic mechanism, but it could also be explained by the existence of common risk factors. The objective of this study was to determine whether COPD patients present greater cardiovascular comorbidity than control subjects and whether COPD can be considered a risk factor per se.

METHODS: 1200 COPD patients and 300 control subjects were recruited for this multicenter, cross-sectional, case-control study.

RESULTS: Compared with the control group, the COPD group showed a significantly higher prevalence of ischemic heart disease (12.5% versus 4.7%; P < 0.0001), cerebrovascular disease (10% versus 2%; P < 0.0001), and peripheral vascular disease (16.4% versus 4.1%; P < 0.001). In the univariate risk analysis, COPD, hypertension, diabetes, obesity, and dyslipidemia were risk factors for ischemic heart disease. In the multivariate analysis adjusted for the remaining factors, COPD was still an independent risk factor (odds ratio: 2.23; 95% confidence interval: 1.18–4.24; P = 0.014).

CONCLUSION: COPD patients show a high prevalence of cardiovascular disease, higher than expected given their age and the coexistence of classic cardiovascular risk factors

Comments: In this study both cases and controls had to be over 40, minimum 10 pack year history and no other respiratory diagnoses. Controls were recruited largely from a group referred for tobacco consults and did not have pulmonary symptoms. This study showed that compared to smokers, smokers with COPD were significantly more likely to have comorbidities except for lung cancer. The rates of lung cancer were very low and the study was powered based on risk of ischemic heart disease. Ischemic heart disease was much higher in those with stage IV versus stage III but not with other groups. In multivariate analysis adjusted for smoking, age, dyslipidemia, hypertension COPD was still a risk factor for ischemic heart disease and for peripheral vascular disease and cerebral vascular disease. The relationship between atherosclerosis and COPD in smokers is compelling and may ultimately be incorporated in management guidelines with regard to screening and treatment paradigms for COPD.

Treatment of COPD by clinical phenotypes. Putting old evidence into clinical practice. M. Miravitlles, J. Jose Soler-Cataluna, M. Calle, J.B. Soriano. Eur Respir J. 2012 Oct 11. [Epub ahead of print]

Abstract: The new GOLD update has moved forward the principles of treatment of stable COPD by including the concepts of symptoms and risks into the decision of therapy; however, no mention of the concept of clinical phenotypes was included. It is recognized that COPD is a very heterogeneous disease and not all patients respond to all the drugs available for treatment. The identification of responders to therapies is crucial in chronic diseases to provide the most appropriate treatment and avoid unnecessary medications. The classically defined phenotypes of chronic bronchitis and emphysema, together with the newly described phenotypes of overlap COPD-asthma and frequent exacerbator allow a simple classification of patients that share clinical characteristics and outcomes and, more importantly, similar responses to existing treatments.These clinical phenotypes can help clinicians identify patients that respond to specific pharmacologic interventions. As an example, frequent exacerbators are the only subjects with an indication for anti-inflammatory treatment in COPD. Among them, those with chronic bronchitis are the only candidates to receive PDE4 inhibitors. Patients with overlap COPD-asthma phenotype show an enhanced response to inhaled corticosteroids and infrequent exacerbators should only receive bronchodilators. These well defined clinical phenotypes could potentially be incorporated into treatment guidelines.

Comment: This article is a very nice review of the utility of current clinical phenotypes that can be used to guide initial therapeutic strategies. While the Gold guidelines current iteration has included risks and symptoms to the treatment guideline paradigm the proposed treatment by clinical phenotypes as outlined in this article is perhaps more user friendly for the practicing clinician. Indeed many clinicians can readily assess and identify clinical phenotypes in their patient population rather than remember the criteria for each quadrant of the current Gold Guideline paradigm. Ultimately however each patient is and individual and therapy should take many factors into consideration.