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New therapies are being developed to target proinflammatory mediators thought to be involved in the pathophysiology of severe asthma. Tralokinumab is an investigational fully human monoclonal antibody that specifically blocks binding of IL-13 to its receptors. Here, we describe the background leading to the design of two Phase III trials, STRATOS 1 and 2 (NCT02161757 and NCT02194699), which aim to provide confirmatory evidence of the efficacy and safety of tralokinumab in patients with asthma that is uncontrolled despite treatment with inhaled corticosteroids and long-acting β2-agonists. These trials will also confirm the validity of periostin and DPP-4, identified in a prior Phase IIb study (NCT01402986), as predictors of an enhanced response to tralokinumab.

Interstitial lung diseases (ILD), including those related to connective tissue disease (CTD), and idiopathic pulmonary fibrosis (IPF) carry high morbidity and mortality. Great efforts are under way to develop and investigate meaningful treatments in the context of clinical trials. However, efforts have been challenged by a lack of validated outcome measures and by inconsistent use of measures in clinical trials. Lack of consensus has fragmented effective use of strategies in CTD-ILD and IPF, with a history of resultant difficulties in obtaining agency approval of treatment interventions. Until recently, the patient perspective to determine domains and outcome measures in CTD-ILD and IPF had never been applied. Efforts described here demonstrate unequivocally the value and influence of patient involvement on core set development. Regarding CTD-ILD, this is the first OMERACT working group to directly address a manifestation/comorbidity of a rheumatic disease (ILD) as well as a disease not considered rheumatic (IPF). The OMERACT 11 proceedings of the CTD-ILD Working Group describe the forward and lateral process to include both the medical and patient perspectives in the urgently needed identification of a core set of preliminary domains and outcome measures in CTD-ILD and IPF.

ObjectiveTo estimate predictors and longterm outcome of interstitial lung disease ILD in patients with polymyositis PM and dermatomyositis DM.MethodsWe conducted a prospective study in which newly diagnosed PMDM patients, regardless of clinical symptoms of pulmonary disease, were investigated with repeated chest radiography, highresolution computed tomography HRCT of the lungs, and pulmonary function test PFT. Clinical, radiologic, and lung function outcome was based on the last followup results.ResultsTwentythree patients with a mean followup period of 35 months were included. Findings on radiographic examination andor PFT compatible with ILD were recorded in 18 patients 78. Patients with ILD had lower lung function, higher radiologic scores, and higher creatine kinase values than those without ILD. All patients were treated with highdose glucocorticoids and other immunosuppressive agents. Two patients died due to ILD, both with active myositis. During the followup, total lung capacity TLC improved in 33, remained stable in 39, and deteriorated in 28. Changes in TLC correlated only partially with HRCT findings, which persisted even after normalizing for lung function.ConclusionILD associated with PMDM is in most cases mild, chronic, and has a nonprogressive course during immunosuppressive treatment. PFT can be normalized during treatment with immunosuppressive therapy, even if radiologic signs of ILD persist. The course of ILD could not be predicted on the first examination. Therefore, myositis patients with ILD need careful evaluation of clinical features as well as PFT and radiologic features during followup.

Flour dust in bakeries is known to cause allergic as well as nonallergic respiratory symptoms. Fungal α-amylase is a commonly used baking additive that has been shown to have allergenic properties. The aim of this study was to investigate any effects on bronchoalveolar lavage (BAL) cells and peripheral blood lymphocytes (PBL) of healthy individuals exposed to airborne wheat flour dust with or without fungal α-amylase added. Fifteen subjects were exposed during 1 hr in an exposure chamber, ten individuals to wheat flour alone and five with α-amylase added. BAL was performed 2–6 weeks before and 1 day after the exposure. BAL cells were differentially counted and flowcytometric analysis of the expression of activation, adhesion, and subset markers on alveolar macrophages (AM) and T cells in BAL fluid and peripheral blood were carried out. Exposure to wheat flour dust increased the total number of cells in BAL fluid from 75.4 (i.q. range 70.4–104.1) to 127.4 (92.1–187.4) cells × 10⁶/L, P < 0.01. There was a significant difference in the change of total BAL cell concentration between the study group exposed to wheat flour only (n = 10; increase with 91.9 × 10⁶/L) and the group exposed to wheat flour with the baking additive fungal α-amylase (n = 5; decrease with 5.4 × 10⁶/L). The exposure level of respirable dust was lower in the group that received α-amylase and the increase in BAL cell concentration showed a positive correlation with the concentration of respirable dust in the exposure chamber (r = 0.80, P < 0.001). The phenotypic analysis of AM indicated an influx of monocytic cells. The results indicate that the concentration of respirable dust, but not α-amylase, is of importance for the recruitment of inflammatory cells to the peripheral airways in healthy individuals exposed to wheat flour dust. Am. J. Ind. Med. 44:75–82, 2003. © 2003 Wiley-Liss, Inc.

Firefighters are exposed to irritating, asphyxiating toxic gases and aerosols. Previous studies indicate that this may result in acute as well as chronic lung function impairment. It is well known that inhalation of organic material can cause alveolitis. The purpose of this study was to investigate whether firefighters repeatedly exposed to fire gases and other combustion products develop inflammatory changes in the lower airways and, if so, what subtype of cells and soluble components accumulate.

Firefighters are exposed to irritating, asphyxiating toxic gases and aerosols. Previous studies indicate that this may result in acute as well as chronic lung function impairment. It is well known that inhalation of organic material can cause alveolitis. The purpose of this study was to investigate whether firefighters repeatedly exposed to fire gases and other combustion products develop inflammatory changes in the lower airways and, if so, what subtype of cells and soluble components accumulate. Thirteen nonsmoking firefighters underwent bronchoalveolar lavage (BAL), and the results were compared to a reference group of 112 nonsmoking healthy volunteers. The firefighters showed lower recovery of instilled lavage fluid (61% vs 72%; P < 0.01) and an increase in the proportion of lymphocytes in that fluid (8.2% vs 5.7%; P < 0.05). Alveolar macrophage fluorescence, which is a sign of uptake of inhaled fluorescent material, rather than a reflection of the degree of inflammation, was increased in two firefighters. Further, the lavage fluid had higher concentrations of native fibronectin (34.6 vs 22.0 μg/L; P < 0.01) and hyaluronic acid (27.7 vs 10.0 μg/L; P < 0.05). This may indicate local cell activation, since the alveolar capillary membrane probably was intact, as indicated by an unaffected albumin concentration. The observed changes in the deep airways are probably caused by exposure to smoke. It cannot be concluded whether these changes are permanent or are part of a natural temporary defense mechanism. Am. J. Ind. Med. 32:332–336, 1997. © 1997 Wiley-Liss, Inc.

The objective of this study was to investigate whether occurrence of pleural plaques is associated with exposure to mineral wool. The occurrence of pleural plaques on routine chest radiographs of 933 persons employed in the mineral wool manufacturing industry and 865 referents was compared. Twelve men from the mineral wool industry had pleural plaques, as against three of the referents (P > 0.05). The occurrence of pleural plaques among men in the mineral wool industry was not associated with an increased exposure to mineral wool or with length of time between start of employment and time of chest radiograph. The results do not support the notion that inhalation of man-made mineral fibers causes pleural plaques. It must, however, be conceded-keeping in mind the limits imposed by the study size-that nor do they provide grounds for refutation of such a hypothesis.

Different ways to describe historic fibre exposure from asbestos-containing friction materials were studied and compared for a group of 103 car and bus mechanics with more than 20 years employment and 15 years of asbestos exposure. A model was constructed to calculate cumulative asbestos exposure from friction materials including duration, intensity and exposure last year. The model is a combination of an additive and a multiplicative model, where an asbestos index was constructed that takes both near field and far field exposure into consideration. The model was based upon data from the international literature and quantitative asbestos measurements performed 1976–1988 in Swedish car repair workshops. The fibres were counted by phase-contrast microscopy with fibre criteria of length >5 μm and aspect ratio ≥3:1. The mechanics' fibre exposure at 398 repair workshops during a period of 48 years were calculated using the model. The mean cumulative exposure was estimated to be 2.6 f ml−1∗ year. The annual cumulative exposure was highest for truck mechanics in the early 1960s. The car mechanics had a time-weighted average fibre exposure range of 0.11 – 0.41 f ml−1(mean 0.21 f ml−1) in 1965 compared to 0.003 – 0.08 f ml−1(mean 0.021 f ml−1in 1985. In order to validate the model, the mechanics' fibre exposure estimated using the model were compared with representative asbestos exposure measurements for car mechanics during the 1960s and the 1970s (correlation coefficient = 0.69). Five lung physiological variables (FVC, TLC, FEV1, TLcoand CV%) were used to study exposure-response relationships. None of the exposure parameters suggested any significant relationship between exposure and decrease in lung function.

A cross-sectional investigation was performed in seven polyurethane foam manufacturing factories. Lung function tests were performed at the factories by spirometric and nitrogen wash-out methods. Sixty-seven persons were investigated before and after the work shift, and exposure to toluene diisocyanate (TDI) was evaluated by subject-carried sampling equipment on the same day. The day mean exposure to TDI was 0.008 mg/ m3 (0.001 ppm). In the non-smokers there was an increased frequency of symptoms from the airways reported in the exposed subjects as compared to the unexposed controls. There were, however, no signs of acute or chronic effects on the lung function measured by spirometric and nitrogen wash-out methods, which could not be explained by smoking.

Exposure to sawdust and its contaminants, e.g., terpenes, may cause respiratory tract and lung parenchymal inflammation. To monitor these changes over time, Sprague-Dawley rats were exposed at one occasion to 2.5 mg sawdust or saline by intratracheal instillation. Flow cytometry analyses were done on bronchoalveolar lavage (BAL) cells. Lung tissue specimens were analyzed histologically and immunohistochemically. After one week, the number of BAL polymorphonuclear leukocytes was increased (P<0.05,N=8), followed at six weeks by increases of macrophages and lymphocytes (bothP<0.01,N=8). Enhanced expressions of class II antigens and complement receptors on macrophages after one week were even more pronounced at six weeks, indicating cellular activation. The BAL findings, also including increased (P<0.001,N=8) concentrations of hyaluronan with progressing changes over time, confirmed the signs of inflammation, as did the histological analysis of the lung tissue specimens with an accumulation of polymorphonuclears, macrophages, and hyaluronan in the interstitium.

Dipyridamole has been shown to induce proliferative activity in heart muscle capillary wall cells in the rat. To test whether this effect is due to direct cellular stimulation we tested the substance in various in vitro systems (human lymphocytes, glial cells and endothelial cells; and bovine endothelial cells). During these conditions dipyridamole did not influence cellular proliferation. In all cell systems tested, uptake of labelled thymidine showed an inhibition by dipyridamole. This confirms the earlier finding that dipyridamole inhibits nucleoside uptake, and extends the finding to human cells.

A 23-year old female who developed a chylothorax as a probable complication after delivery is described and a possible mechanism is proposed. Conservative treatment was unsuccessful and the surgical management was complicated by an anatomical variation with the thoracic duct presenting as a plexiform system instead of a single duct.

The hearts of rats treated with dipyridamole were studied by light microscope autoradiography and measurement of tissue radioactivity after intravenous injection of 3H-thymidine. Total tissue radioactivity was significantly increased in the hearts of the dipyridamole-treated animals. Only capillary wall cells were labelled in the autoradiograms. The observations indicate a proliferation of capillary wall cells, suggesting a neoformation of myocardial capillaries during dipyridamole treatment.

Different ways to describe historic fibre exposure from asbestos-containing friction materials were studied and compared for a group of 103 car and bus mechanics with more than 20 years employment and 15 years of asbestos exposure. A model was constructed to calculate cumulative asbestos exposure from friction materials including duration, intensity and exposure last year. The model is a combination of an additive and a multiplicative model, where an asbestos index was constructed that takes both near field and far field exposure into consideration. The model was based upon data from the international literature and quantitative asbestos measurements performed 1976–1988 in Swedish car repair workshops. The fibres were counted by phase-contrast microscopy with fibre criteria of length <5 μm and aspect ratio ≥3:1. The mechanics fibre exposure at 398 repair workshops during a period of 48 years were calculated using the model. The mean cumulative exposure was estimated to be 2.6 f ml−1 * year. The annual cumulative exposure was highest for truck mechanics in the early 1960s. The car mechanics had a time-weighted average fibre exposure range of 0.11–041 f ml−1 (mean 0.21 f ml−1) in 1965 compared to 0.003–0.08 f ml−1 (mean 0.021 f ml−1) in 1985. In order to validate the model, the mechanics fibre exposure estimated using the model were compared with representative asbestos exposure measurements for car mechanics during the 1960s and the 1970s (correlation coefficient =0.69). Five lung physiological variables (FVC, TLC, FEV1 TLco and CV%) were used to study exposure-response relationships. None of the exposure parameters suggested any significant relationship between exposure and decrease in lung function.