Residual Disease in Patients with Axial Spondyloarthritis: A Post-Hoc Analysis of the QUASAR Study.

In this study, we evaluated the presence of residual disease in patients with axial spondyloarthritis (axSpA) in remission/low disease activity (LDA) status. This cross-sectional post-hoc analysis of the QUASAR study involving 23 rheumatology centres across Italy included adults with axSpA classified according to the Assessment of SpondyloArthritis International Society criteria. Patients with inactive disease (score < 1.3) or at least LDA status (score < 2.1) at baseline visit according to Ankylosing Spondylitis Disease Activity Score were investigated to evaluate how residual disease activity impacts patients' quality of life. They were assessed using the Ankylosing Spondylitis Quality of Life (ASQoL) and EuroQoL 5-Dimension 5-Level (EQ-5D-5L) questionnaires. This study included 480 patients with axSpA (mean age, 47.5 ± 12.9 years, 64% male). In total, 123 patients (25.6%) had inactive disease and 262 (54.6%) had at least LDA. Using the ASQoL, ranges of 10−25% and 20−40% of patients with inactive disease and with LDA status, respectively, experienced tiredness/fatigue. Despite being classified with inactive disease, 48.8% of patients reported light pain/discomfort according to the EQ-5D-5L, with 4.1% reporting moderate pain/discomfort, whereas 55.7% of patients with LDA reported light pain/discomfort and 13% had moderate pain/discomfort. Using the ASQoL questionnaire, in patients with at least LDA, a higher proportion of women compared with males and a higher proportion of patients > 48 years of age (vs. patients ≤ 48 years) experienced tiredness. In this post-hoc analysis, ≥25% of axSpA patients in remission/LDA status were still burdened by residual disease, mainly characterised by pain and fatigue.

Extra-Articular Manifestations and Comorbidities in Psoriatic Disease: A Journey Into the Immunologic Crosstalk.

Psoriatic arthritis (PsA) is a chronic inflammatory disease primarily affecting peripheral and axial joints, with the possible presence of extra-articular manifestations (EAMs), such as psoriasis, uveitis, and inflammatory bowel disease. Recently, the concept of psoriatic disease (PsD) has been proposed to define a systemic condition encompassing, in addition to joints and EAMs, some comorbidities (e.g., metabolic syndrome, type II diabetes, hypertension) that can affect the disease outcome and the achievement of remission. EAMs and comorbidities in PsA share common immunopathogenic pathways linked to the systemic inflammation of this disease; these involve a broad variety of immune cells and cytokines. Currently, various therapeutics are available targeting different cytokines and molecules implicated in the inflammatory response of this condition; however, despite an improvement in the management of PsA, comprehensive disease control is often not achievable. There is, therefore, a big gap to fill especially in terms of comorbidities and EAMs management. In this review, we summarize the clinical aspects of the main comorbidities and EAMs in PsA, and we focus on the immunopathologic features they share with the articular manifestations. Moreover, we discuss the effect of a diverse immunomodulation and the current unmet needs in PsD.

Use of Ultrasonography to Discriminate Psoriatic Arthritis from Fibromyalgia: A Post-Hoc Analysis of the ULISSE Study.

In psoriatic arthritis (PsA) patients with concomitant chronic widespread pain, the differential diagnosis with fibromyalgia syndrome (FMS) can be challenging. We evaluated whether ultrasound (US) examination of entheseal sites can distinguish pain from (PsA) enthesitis versus FMS. PsA and FMS patients underwent clinical evaluation and gray-scale (GS; B-mode) and power Doppler (PD) US examination of the entheses. At least one enthesis with GS- and PD-mode changes was found in 90% and 59.3% of PsA patients (n = 140) and 62.7% and 35.3% of FMS patients (n = 51), respectively. GS and PD identified changes in 49.5% and 19.2% of the 840 PsA entheses and 22.5% and 7.9% of the 306 FMS entheses, respectively. Receiver operating characteristic curve analysis showed an area under the curve of 0.77 and 0.66 for B- and PD-mode, respectively, 3.5 being the best cut-off GS-score to discriminate the two conditions. Multivariate regression showed that Achilles and proximal patellar tendon enthesitis (B-mode) were strongly associated with PsA (odds ratio, ~2). Principal component analysis (B-mode) confirmed that PsA patients have a higher number of involved entheses and patterns of entheseal involvement than FMS patients. US evaluation of the entheses may help differentiate chronic widespread pain from PsA versus FMS.

Severe uncontrolled asthma with bronchiectasis: a pilot study of an emerging phenotype that responds to mepolizumab.

BACKGROUND: Asthma and bronchiectasis are different conditions that frequently coexist. The prevalence of bronchiectasis rises considerably in subjects with severe asthma (25%-51%). OBJECTIVE: We evaluated the clinical and biological efficacy of mepolizumab on our pilot population of severe uncontrolled asthmatics with bronchiectasis not related to other pathologies. PATIENTS AND METHODS: Four patients with severe uncontrolled asthma and diagnosed as bronchiectasis were recruited and started biological treatment with mepolizumab. Standard investigations were performed in all four patients at baseline (T0), after 3 months (T1) and after 1 year (T2) of treatment. RESULTS: After 1 year (T2) of therapy with mepolizumab, patients showed a significant increment of asthma control test value (12±1.1 vs 24.5±0.3, P<0.01), a reduction of the number of exacerbations/year (5±0.7 vs 0.75±0.75, P<0.01), an increase of pre-bronchodilator FEV1 (1,680±500 vs 1,860±550 mL, P<0.01) and a reduction of eosinophils in blood (0.75±0.14 vs 0.12±0.02 cells/µL, P<0.01), in the sputum (9.6%±2.1% vs 5.6%±2.7%, P<0.05) and in nasal cytology (++ vs +). CONCLUSION: The efficacy of mepolizumab in terms of reduction of inflammation and increase of control that we observed in our patients might suggest that targeting the IL-5 in severe eosinophilic asthma with bronchiectasis may be a good therapeutic strategy.

Long-term effects of inhaled corticosteroids on sputum bacterial and viral loads in COPD.

Inhaled corticosteroid-containing medications reduce the frequency of COPD exacerbations (mainly infectious in origin) while paradoxically increasing the risk of other respiratory infections. The aim was to determine the effects of inhaled corticosteroids on airway microbial load in COPD patients and evaluate the influence of the underlying inflammatory profile on airway colonisation and microbiome.This is a proof-of-concept prospective, randomised, open-label, blinded endpoint study. Sixty patients with stable moderate COPD were randomised to receive one inhalation twice daily of either a combination of salmeterol 50 µg plus fluticasone propionate 500 µg or salmeterol 50 µg for 12 months. The primary outcome was the change of sputum bacterial loads over the course of treatment.Compared with salmeterol, 1-year treatment with salmeterol plus fluticasone was associated with a significant increase in sputum bacterial load (p=0.005), modification of sputum microbial composition and increased airway load of potentially pathogenic bacteria. The increased bacterial load was observed only in inhaled corticosteroid-treated patients with lower baseline sputum or blood eosinophil (≤2%) levels but not in patients with higher baseline eosinophils.Long-term inhaled corticosteroid treatment affects bacterial load in stable COPD. Lower eosinophil counts are associated with increased airway bacterial load.

Iron laden macrophages in idiopathic pulmonary fibrosis: the telltale of occult alveolar hemorrhage?

RATIONALE: A number of observations suggest that iron accumulates in the lungs of patients with idiopathic pulmonary fibrosis (IPF) with vascular abnormalities, including pulmonary hypertension. OBJECTIVES: The aim of this study was to determine the prevalence and intensity of accumulation of alveolar epithelial lining fluid (ELF) iron and of alveolar macrophage hemosiderin in IPF and its relationship with disease severity. METHODS: Forty seven IPF patients and 14 healthy controls were retrospectively evaluated for iron accumulation in the lower respiratory tract using total iron spectrophotometric measures and for hemosiderin accumulation using the Perls' stain with the Golde score. MEASUREMENTS AND MAIN RESULTS: Total iron levels in ELF were significantly increased in IPF patients compared to non-smoking controls (p < 0.05); there were no differences with healthy smokers (p = 0.2). Hemosiderin accumulation in alveolar macrophages was similar in never smoking and ever smoking IPF patients (p = 0.5), was significantly higher in IPF patients than in both smoking and non-smoking healthy controls (p < 0.05, all comparisons) and was positively correlated with echocardiographic estimates of pulmonary artery systolic pressure (p < 0.05) and with increasing disease severity scores (p < 0.05). CONCLUSIONS: The data show exaggerated accumulation of iron in IPF broncho-alveolar ELF and alveolar cells with no association with tobacco smoke, thus suggesting, occult pulmonary hemorrhage as a likely cause.

Airway basal cell vascular endothelial growth factor-mediated cross-talk regulates endothelial cell-dependent growth support of human airway basal cells.

The human airway epithelium is a pseudostratified heterogenous layer comprised of ciliated, secretory, intermediate, and basal cells. As the stem/progenitor population of the airway epithelium, airway basal cells differentiate into ciliated and secretory cells to replenish the airway epithelium during physiological turnover and repair. Transcriptome analysis of airway basal cells revealed high expression of vascular endothelial growth factor A (VEGFA), a gene not typically associated with the function of this cell type. Using cultures of primary human airway basal cells, we demonstrate that basal cells express all of the three major isoforms of VEGFA (121, 165 and 189) but lack functional expression of the classical VEGFA receptors VEGFR1 and VEGFR2. The VEGFA is actively secreted by basal cells and while it appears to have no direct autocrine function on basal cell growth and proliferation, it functions in a paracrine manner to activate MAPK signaling cascades in endothelium via VEGFR2-dependent signaling pathways. Using a cytokine- and serum-free co-culture system of primary human airway basal cells and human endothelial cells revealed that basal cell-secreted VEGFA activated endothelium to express mediators that, in turn, stimulate and support basal cell proliferation and growth. These data demonstrate novel VEGFA-mediated cross-talk between airway basal cells and endothelium, the purpose of which is to modulate endothelial activation and in turn stimulate and sustain basal cell growth.

Markers of anti-oxidant response in tobacco smoke exposed subjects: a data-mining review.

Tobacco smoke exposure is the cause of exaggerated inflammatory responses and tissue destruction leading to chronic bronchitis and emphysema. A number of studies have used biochemical and immunological technologies to identify biomarkers of severity, risk and pharmacological target of disease. Recently, genomic and proteomic studies have been carried out to explore tobacco smoke-induced lung damage mechanisms. Eight of these studies, including 81 healthy non-smokers, 138 healthy smokers and 24 smokers with COPD, had open platform generated data available online and were reviewed in order to identify markers of smoke-induced damage by analyzing differential gene and protein expression in healthy individuals exposed to tobacco smoke in comparison with chronic obstructive pulmonary disease (COPD) smokers and healthy non-smokers. To this end the Ingenuity Pathways Analysis, a web-based application enables identifying the main biological functions and pathways, was used. The pathway most significantly associated with healthy smokers was the Nrf2-mediated Oxidative Stress Response (p-value < 0.01): out of the 22 genes/proteins identified in healthy smokers, 19 were up-regulated and three down-regulated, compared to non-smokers. Interestingly, four genes/proteins of the same pathway were differentially regulated in COPD, one up-regulated and three down-regulated, compared to healthy smokers. Moreover, in the comparison between COPD and healthy smokers, our analysis showed that the most relevant pathway was the Mitochondrial Dysfunction (p-value < 0.01) with 12 differentially regulated genes/proteins. This data-mining review supports the notion that Nrf2-regulated anti-oxidant genes play a central role in protection against tobacco smoke toxic effects and may be amenable to use as COPD risk biomarkers. Furthermore, this review suggests that mitochondrial dysfunction may be involved in the development of COPD.

Metabolic syndrome and risk of pulmonary involvement.

Metabolic syndrome (MS) is a complex disorder recognized clinically by the findings of abdominal obesity, elevated triglycerides, atherogenic dyslipidaemia, elevated blood pressure, high blood glucose and/or insulin resistance. It is associated with a pro-thrombotic and a pro-inflammatory state. A growing body of evidence suggests that individuals in the community with moderate airflow limitation may have co-existing systemic inflammation with this background. Therefore, we examined a population of 237 patients with metabolic disorder for the concomitant presence of functional pulmonary involvement, as assessed by FEV(1) and FVC impairment. Criteria for the identification of the MS included 3 or more of the following: waist circumference: (>102 cm in men, >88 cm in women), triglycerides levels (> or =150 mg/dl), high-density lipoprotein cholesterol levels (<40 mg/dl in men, <50 mg/dl in women), blood pressure (> or =135/> or =85 mmHg), and fasting glucose levels (>100 mg/dl). 119 subjects were diagnosed MS. Non-smokers patients suffering from MS presented lower spirometric values, with a trend to ventilatory restrictive more than obstructive pattern. Also in smokers patients with MS there was a trend to harmonic decrease in FEV(1) and FVC but not in FEV(1)/FVC ratio, although the changes did not reach statistical significance. Mainly abdominal circumference, and also insulin resistance were retained as independent predictors of both FEV(1) and FVC changes. However, HDL-C was the strongest predictor of FEV(1) and FVC changes, with an inverse association.

Biomarkers of lung damage associated with tobacco smoke in induced sputum.

Cigarette smoking has been causally linked several diseases, primarily lung cancer and chronic obstructive lung disease (COPD). The diagnosis of COPD currently involves an assessment of smoking and/or occupational exposures, a history of cough, sputum and dyspnea and spirometric measures of airflow obstruction and since spirometric measures take long follow up times to detect significant changes, surrogate measures of outcome capable of predicting long-term health changes have been sought for. These include biomarkers of oxidative stress, inflammation and tissue damage in sputum, bronchoalveolar lavage, exhaled breath and serum. Published biomarker studies have not always accurately compared patients with COPD with age-matched cigarette smokers and non-smoking normal subjects without significant airflow limitation, also comparable for other exposures. Consequently, the interpretation of biomarker association studies is somewhat difficult. The purpose of this narrative review is to summarize publications reporting cellular, soluble or volatile marker of obstructive lung disease in populations of healthy non-smokers and healthy smokers, in order to determine whether the biomarkers examined could be specifically associated with exposure to tobacco smoke rather than with inflammation and airway hyper-reactivity. As induced sputum has been the most widely used investigative tool, this review has been aimed at assessing induced sputum biomarkers, referring to lung biopsy, bronchoalveolar lavage and exhaled breath markers as supporting evidence for biomarkers associations identified with induced sputum studies.

A pilot comparison of helium dilution and plethysmographic lung volumes to assess the impact of a long-acting bronchodilator on lung hyperinflation in COPD.

BACKGROUND: Currently, two methods for measuring TLC, RV, and FRC are used in clinical pulmonary function laboratories: body plethysmography and helium dilution. However, these methods are not interchangeable. In moderate-to-severe airflow obstruction, dilution method tends to underestimate and body plethysmography tends to overestimate RV. PURPOSE: In 21 patients suffering from COPD (basal FEV(1): 56.69+/-13.64), we investigated whether the two methods of measuring FRC and RV could respond differently to a 2-week treatment with tiotropium 18 microg/day. MAIN RESULTS: Tiotropium induced a significant increase in FEV(1) and FVC but not in IC. At baseline, FRC(pleth), RV(pleth) and TLC(pleth) were higher than FRC(He), RV(He) and TLC(He). At the end of the study FRC(pleth), RV(pleth) and TLC(pleth) decreased and FRC(He), RV(He) and TLC(He) increased but only changes in FRC(pleth) and RV(pleth) were statistically significant. CONCLUSION: The use of body plethysmography seems to be more appropriate in clinical trials aimed at assessing the impact of a therapeutic procedure in patients with COPD and lung hyperinflation.

Relaxant effect of brain natriuretic peptide in nonsensitized and passively sensitized isolated human bronchi.

Brain natriuretic peptide (BNP) relaxes guinea pig tracheal smooth muscle in vitro and is effective in preventing ovalbumin-induced bronchoconstriction and microvascular leakage in guinea pigs in vivo. Nonetheless, published studies on BNP in human airways in vitro are still lacking in the literature. The aim of this study was to investigate the effect of BNP in isolated human bronchi. The relaxant effect of BNP (1 nM to 10 microM) was assessed in nonsensitized and in passively sensitized human bronchial airways pre-contracted with submaximal concentration (EC(70)) of carbachol or histamine. At the end of the experiment, papaverine (500 microM) was then added. BNP induced a weak relaxant activity on carbachol-contracted bronchi in nonsensitized (relaxation: 4.23+/-0.51%) and passively sensitized bronchi (relaxation: 11.31+/-2.22%). On the other hand, BNP induced a relaxant activity on His-contracted bronchi in nonsensitized (relaxation: 42.52+/-9.03%) and in passively sensitized (relaxation: 60.57+/-9.58%). All these findings are a clear documentation of the modest relaxant role of BNP in asthma and, likely, COPD.

Long-acting beta(2) agonists in asthma and allergic rhinitis.

BACKGROUND: Long-acting beta(2) agonists (LABAs) are effective second-line bronchodilator controller agents in asthma, although they may also increase the risk of hospitalization and asthma-related death in certain situations. Despite the interesting findings obtained with short-acting beta(2) agonists (SABAs), negative studies are available with LABAs in the treatment of allergic rhinitis. This is quite surprising given that there is now clear documentation of the link between asthma and allergic rhinitis. OBJECTIVE: The aim of this review is to examine the role of beta(2) agonists in patients with asthma who also suffer from allergic rhinitis and to try to explain the differences observed between SABAs and LABAs in rhinitis. METHODS: SCOPUS, GOOGLE SCHOLAR and MEDLINE were searched for abstracts and papers; the search was completed in March 2008. No restriction was placed on language. CONCLUSION: The intriguing united airway concept led to the hypothesis that common therapies may influence both and asthma and allergic rhinitis. Consequently, better designed studies with LABAs in allergic rhinitis are now mandatory. In particular, further studies are necessary to investigate clinically relevant anti-inflammatory synergy between inhaled corticosteroids and LABAs in upper airways. It will also be interesting to assess whether ultra-LABAs (once-daily LABAs) are active in allergic rhinitis, although the information we have seems to exclude a role for these agents.

Bacterial extracts for the prevention of acute exacerbations in chronic obstructive pulmonary disease: a point of view.

Given the high prevalence of chronic obstructive pulmonary disease (COPD), the impact of exacerbations on quality of life, and the costs incurred, effective ways for the prevention of exacerbations, and for reductions in the severity and duration of COPD symptoms are needed. Bacterial immunostimulation has been advocated as a management strategy in COPD for the purposes of preventing acute exacerbations. In particular, it suggests that the use of oral multicomponent vaccines may reduce the severity and duration of acute episodes. The way in which bacterial extracts may exert their effects is not fully understood although a number of possible specific mechanisms have been suggested. Given the high prevalence of COPD worldwide and the high cost of acute exacerbations, some cost-effectiveness analyses suggest that bacterial immunostimulants may become a key element in the improved control of this condition. Nonetheless, larger and longer clinical trials are needed to investigate efficacy before oral vaccination could be recommended as part of the routine clinical management of COPD, mainly in advanced COPD. It remains also to be investigated whether this protective effect may be additive to the other treatments. In any case, it is well known that for Streptococcus pneumoniae, non-typable Haemophilus influenzae and Moraxella catarrhalis, recurrent infections occur because of strain heterogeneity. Therefore, a single or even multiple strain vaccine with a killed whole cell formulation is possibly not the ideal vaccine. Moreover, the method of inactivation can affect the immunogenicity of essential antigens through denaturation. For this reason, the efficacy of bacterial immunostimulants should not only be assessed but also compared.