Lower corticosteroid skin blanching response is associated with severe COPD

Abstract

Background: Chronic obstructive pulmonary disease (COPD) is characterized by chronic airflow limitation caused by ongoing inflammatory and remodeling processes of the airways and lung tissue. Inflammation can be targeted by corticosteroids. However, airway inflammation is generally less responsive to steroids in COPD than in asthma. The underlying mechanisms are yet unclear. This study aimed to assess whether skin corticosteroid insensitivity is associated with COPD and COPD severity using the corticosteroid skin blanching test.

Methods: COPD patients GOLD stage I-IV (n = 27, 24, 22, and 16 respectively) and healthy never-smokers and smokers (n = 28 and 56 respectively) were included. Corticosteroid sensitivity was assessed by the corticosteroid skin blanching test. Budesonide was applied in 8 logarithmically increasing concentrations (0-100 μg/ml) on subject's forearm. Assessment of blanching was performed after 7 hours using a 7-point scale (normal skin to intense blanching). All subjects performed spirometry and body plethysmography.

Results: Both GOLD III and GOLD IV COPD patients showed significantly lower skin blanching responses than healthy never-smokers and smokers, GOLD I, and GOLD II patients. Their area under the dose-response curve values of the skin blanching response were 586 and 243 vs. 1560, 1154, 1380, and 1309 respectively, p<0.05. Lower FEV1 levels and higher RV/TLC ratios were significantly associated with lower skin blanching responses (p = 0.001 and p = 0.004 respectively). GOLD stage I, II, III and IV patients had similar age and packyears.

Conclusions: In this study, severe and very severe COPD patients had lower skin corticosteroid sensitivity than mild and moderate COPD patients and non-COPD controls with comparable age and packyears. Our findings together suggest that the reduced skin blanching response fits with a subgroup of COPD patients that has an early-onset COPD phenotype.

Trial registration: ClinicalTrials.gov NCT00807469 NCT00848406 NCT00850863.

Conflict of interest statement

Competing Interests: The authors have the following interests. This study was partly funded by grant T1-108 from Top Institute Pharma, with partners Nycomed and GlaxoSmithKline. The University of Groningen received funding for NHTTH from GlaxoSmithKline, Boehringer Ingelheim, Nycomed, and Chiesi. The University of Groningen received fees for consultancies for DSP of AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Nycomed, TEVA, and received grants from AstraZeneca and Chiesi. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Blanching of the skin as a result of vasoconstriction, 7 hours after application of budesonide in increasing concentrations.

Figure 2. Skin blanching responses in healthy controls and COPD patients GOLD stages I–IV.

AUC  =  area under the dose-response curve. Values are expressed as median [range]. ** significantly different from healthy never-smokers, healthy smokers, GOLD I and GOLD II patients (p-value

Figure 3. Dose-response curves of budesonide in healthy controls and COPD patients GOLD stages I–IV.

Values are expressed as mean ± SEM.

Figure 4. Corticosteroid treatment and skin blanching response in COPD patients.

AUC  =  area under the dose-response curve, CS  =  corticosteroids, ICS  =  inhaled corticosteroids, OCS  =  oral corticosteroids.