Background: Many patients with severe asthma are overweight or obese, often attributed to unintentional weight gain as a side effect of oral corticosteroids (OCSs). Anti-IL-5/5Ra biologics... Show moreBackground: Many patients with severe asthma are overweight or obese, often attributed to unintentional weight gain as a side effect of oral corticosteroids (OCSs). Anti-IL-5/5Ra biologics significantly reduce OCS use, but their long-term effects on weight are unknown.Objectives: To examine (1) weight change up to 2 years after anti-IL-5/5Ra initiation in subgroups on the basis of maintenance OCS use at start of treatment and (2) whether cumulative OCS exposure before or changes in OCS exposure during treatment are related to weight change.Methods: Real-world data on weight and cumulative OCS dose from adults included in the Dutch Registry of Adult Patients with Severe asthma for Optimal DIsease management before and at least 2 years after starting anti-IL-5/5Ra were analyzed using linear mixed models and linear regression analyses.Results: For the included 389 patients (55% female; mean body mass index, 28 +/- 5 kg/m(2); 58% maintenance OCS), mean weight decreased -0.27 kg/y (95% CI, -0.51 to -0.03; P = .03), with more weight loss in patients with maintenance OCS use than in those without maintenance OCS use (-0.87 kg/y [95% CI, -1.21 to -0.52; P < .001] vs +0.54 kg/y [0.26 to 0.82; P < .001]). Greater weight loss at 2 years was associated with higher cumulative OCS dose in the 2 years before anti-IL-5/5Ra initiation (beta = -0.24 kg/g; 95% CI, -0.38 to -0.10; P < .001) and, independently, greater reduction in cumulative OCS dose during follow-up (beta = 0.27 kg/g; 95% CI, 0.11 to 0.43; P < .001).Conclusions: Anti-IL-5/5Ra therapy is associated with long-term weight reduction, especially in patients with higher OCS exposure before treatment and those able to reduce OCS use during treatment. However, the effect is small and does not apply to all patients, and so additional interventions seem necessary if weight change is desired. Show less
John-Schuster, G.; Kleijn, S. de; Wijck, Y. van; Kremer, V.; Smits, H.H.; Pieper, M.P.; ... ; Taube, C. 2017
This thesis focuses on the relationship between smoking and macrophages in chronic obstructive pulmonary disease (COPD), and on treatment with inhaled corticosteroids (ICS). Macrophages play an... Show moreThis thesis focuses on the relationship between smoking and macrophages in chronic obstructive pulmonary disease (COPD), and on treatment with inhaled corticosteroids (ICS). Macrophages play an important role in COPD, and constitute a heterogeneous population with pro- (Mf1) and anti-inflammatory (Mf2) cells. This thesis evaluated YKL-40 and CD163 as markers for Mf1 and Mf2, respectively. Peripheral airways contained more CD163-positive Mf2 compared to central airways. Smoking cessation skewed the macrophage phenotype towards Mf2 in the peripheral airways, but did not influence YKL-40 levels in sputum. Whereas smoking can induce structural alterations in extracellular matrix (ECM) components in the airways, no differences in ECM components in bronchial biopsies were found between current and ex-smokers with COPD. ICS treatment attenuates lung function decline and decreases airway inflammation in a subgroup of COPD patients. However, long-term ICS treatment did not change YKL-40 levels in sputum and serum. ICS increased deposition of several ECM proteins in the airways, which was correlated with improved lung function, suggesting prevention of airway collapse. Withdrawal of ICS after long-term treatment induced a relapse in lung function decline and increased airway inflammation in bronchial biopsies and sputum, suggesting that benefits of ICS do not persist after discontinuation of ICS. Show less
Ravensberg, A.J.; Slats, A.M.; Wetering, S. van; Janssen, K.; Wijngaarden, S. van; Jeu, R. de; ... ; Hiemstra, P.S. 2013
Asthma is characterized by chronic airway inflammation and airway hyperresponsiveness. Deep inspirations affect airway narrowing and may therefore play a role in airway hyperresponsiveness in... Show moreAsthma is characterized by chronic airway inflammation and airway hyperresponsiveness. Deep inspirations affect airway narrowing and may therefore play a role in airway hyperresponsiveness in asthma. The studies described in this thesis were all directed at further elucidating the (patho)physiological mechanism underlying deep inspiration-induced bronchodilation or to restoring this protective mechanism in asthma. We showed that deep inspiration-induced bronchodilation is reduced in asthma and that this reduction is related to increased numbers of CD4+ lymphocytes in the bronchial submucosa and to increased numbers of mast cells in airway smooth muscle bundles in bronchial biopsies. In addition, impaired deep inspiration-induced bronchodilation is related to lower expression of several smooth muscle proteins (calponin, desmin, and MLCK) in bronchial biopsies, whereas lung function and airway hyperresponsiveness wa s related to higher expression of alpha-SM-actin, desmin and elastin. Further, pulmonary congestion had no influence on airway responses to deep inspiration as measured in patients with mitral valve disease. A course of high-dose corticosteroid treatment increased bronchodilation following deep inspiration in patients with asthma, whereas treatment with tiotropium for 21 days had no effect on airway responses to deep inspiration. Positive-pressure inflation of the lungs reduced airway narrowing, even in patients who showed no airway dilation following an active deep inspiration. Show less
This thesis comprises data from the GLUCOLD study (Groningen Leiden Universities and Corticosteroids in Obstructive Lung Disease), a prospective study in COPD. In chapter 2 is shown that airflow... Show moreThis thesis comprises data from the GLUCOLD study (Groningen Leiden Universities and Corticosteroids in Obstructive Lung Disease), a prospective study in COPD. In chapter 2 is shown that airflow limitation, asthma-like components, exhaled nitric oxide and sputum inflammatory cell counts offer separate and additive information about the pathophysiological condition of COPD. Chapter 3 shows that uneven distribution of ventilation and airway closure in stable COPD are associated with neutrophilic inflammation in bronchial biopsies and bronchoalveolar lavage fluid. Chapter 4 and 5 show that ex-smokers with COPD have higher bronchial CD4+ and plasma cell numbers, and less bronchial epithelial mucin stores, proliferating cells, and squamous cell metaplasia than current smokers, whereas neutrophil, macrophage, and CD8+ cell numbers are not different between both groups. Bronchial inflammation and epithelial changes are associated with duration of smoking cessation. Chapter 6 shows that long-term treatment with inhaled corticosteroids in COPD reduces bronchial T-lymphocyte and mast cell numbers, whilst increasing bronchial epithelial integrity and bronchial eosinophil numbers. This is accompanied by a reduced FEV1 decline and improved airway hyperresponsiveness, dyspnea and quality of life. Discontinuation of inhaled corticosteroids at 6 months leads to a relapse of bronchial inflammation and clinical outcome. Show less
Airways from asthmatic subjects are more responsive to bronchoconstrictive stimuli than airways from healthy subjects. Airway smooth muscle (ASM) cells mediate contraction of the airways by... Show moreAirways from asthmatic subjects are more responsive to bronchoconstrictive stimuli than airways from healthy subjects. Airway smooth muscle (ASM) cells mediate contraction of the airways by responding to the bronchoconstrictive stimuli, which was thought to be the primary role of ASM cells. In this thesis, we have addressed the role of the secretory capacity of ASM cells in the regulation of airway inflammation in asthma. Using cultures, we have shown that ASM cells release various chemokines (eotaxin, eotaxin-3 and IL-8) involved in the recruitment of inflammatory cells in response to Th2 cytokines and the antimicrobial peptide LL-37. Also airway epithelial cells produce various chemokines in response to Th2 cytokines dependent on their status of differentiation. The IL-8 release by ASM cells is inhibited by the steroid budesonide whereas the combination of this steroid with the beta2-agonist formoterol (a combination often used by patients with asthma) did not further enhance the inhibitory effect. This suggests that other therapies should be developed to fully inhibit chemokine release by ASM cells. Our studies have helped to gain more insight into the role of ASM cells in airway inflammation in asthma and have led to further important research questions that remain to be addressed. Show less
Three aspects of airway inflammation in asthma were investigated in this thesis: proof of concept, monitoring and management. In chapter 2 is shown that IL-5 is mainly effective in the circulation.... Show moreThree aspects of airway inflammation in asthma were investigated in this thesis: proof of concept, monitoring and management. In chapter 2 is shown that IL-5 is mainly effective in the circulation. In chapter 3 is shown that steroids improve airway hyperresponsiveness, sputum eosinophils, and NO. The changes were not related. This suggests that these markers may provide different information when monitoring anti-inflammatory treatment in asthma. In chapter 4 is shown that alpha-2-macroglobulin is an appropriate marker for measuring microvascular leakage in sputum. This "dual induction" model may used when testing the antiexudative effect of drugs. Chapter 5 demonstrated that the annual decline in FEV1 is related with CD8+ cells. This suggests that inflammatory phenotypes in asthma may have prognostic relevance. In chapter 6 is shown that PEF-variability provides information about asthma severity. Therefore, the current guidelines for the treatment of asthma can be improved by including PEF-variability. In chapter 7 is shown that anti-IgE improves PEF, diminishes allergen responses and is paralleled by a reduction in eosinophils in biopsies and sputum and a decline in IgE+ cells. This suggests that the clinical benefits of anti-IgE in asthma may be explained by a decrease in eosinophilic inflammation and IgE bearing cells. Show less
