Corticosteroids in SARS-COV2 infection: certainties and uncertainties in clinical practice.

INTRODUCTION: The SARS-COV-2 pandemic is a worldwide public health problem due to the large medical burden and limited number of therapies available. Corticosteroids have a rather unclear efficacy in viral non-SARS-COV-2 pneumonias and therefore their use is not universally recommended. In SARS-COV-2 pneumonia however, it is expected that they can reduce the deleterious consequences of the virus-related systemic inflammation. AREAS COVERED: a MEDLINE search covering the period 1995-2020 was completed to identify relevant papers. SARS-COV-2 pathogenesis is very complex and is represented by the interplay of many cytokine-driven inflammation pathways. Its most severe form so called cytokine storm, is an exaggerate reaction of the host infected by the virus rapidly resulting in multiple organ dysfunction (MODS). Corticosteroids have the potential to blunt the inflammation response in such patients, but their efficacy is not the same for all patients. Further on the certainties and uncertainties regarding the efficacy of this therapy in SARS-COV-2 pneumonia are discussed. EXPERT OPINION: In patients with severe SARS-COV-2 pneumonia, corticosteroids can be efficacious, but it is still not clear if they can be safely used in patients with comorbid cardiovascular disease or how the optimal duration of therapy can be established.

Checkpoint inhibitors in NSCLC for the elderly: current challenges and perspectives.

Introduction: In the elderly non-small cell lung cancer (NSCLC) is more commonly diagnosed in advanced stages. Conservative therapy including chemotherapy in this age group might be challenging because one of the criteria for its indication is the appropriate functional status, and in the elderly this is more difficult to ascertain. Checkpoint inhibitors are recent therapies found to be effective alone or in combinations in patients with advanced NSCLC, but little is known about their efficacy and their safety in such patients.Areas covered: We review clinical studies of checkpoint inhibitors in patients with advanced NSCLC in an attempt to identify peculiarities related to their use in the elderly. The clinical studies discussed enrolled a significant proportion of elderly patients and for some compounds, post-hoc analysis in the elderly was performed. Efficacy data supports the use of such compounds in the elderly and the safety profile is acceptable for all molecules discussed.Expert opinion: In the elderly with advanced NSCLC, checkpoint inhibitors are efficacious and well tolerated and may be appropriate for use in patients with an increased impaired functional status. Furthermore, in this category of patients this therapy may be used as a neoadjuvant therapy in order to improve the resectability of the tumor.

Triple fixed inhaled therapy in frequent chronic obstructive pulmonary disease exacerbators: potential advantages for various degrees of airways obstruction.

INTRODUCTION: Inhaled therapies are the therapeutic mainstay in stable chronic obstructive pulmonary disease (COPD). They are represented by long-acting bronchodilators (anticholinergics or beta2-agonists) and by inhaled corticosteroids, currently available as a monotherapy or as combination therapies in one inhaler. Combinations of anticholinergics and beta2 agonists or beta2 agonists and inhaled corticosteroids are widely used per the prescription guidelines. The advantage of them are related with higher adherence and better acceptability by the patients as compared to both components dosed with individual inhalers. Bronchodilator combinations have also been demonstrated to exhibit a superior efficacy due to their synergistic mechanism of action when compared to either monotherapy. Triple therapies with anticholinergic-beta2 agonist-inhaled corticosteroid have been under investigation over the last few years and recently one such product became available in the EU for the treatment of stable COPD. Areas covered: The the FULFIL trial (Lung FUnction and quality of LiFe assessment in COPD with closed trIpLe therapy) investigated the efficacy and safety of fluticasone/vilanterol/umeclidinium once daily therapy in COPD patients. Expert opinion: The results discussed in this paper support the use of this combination in advanced COPD but also in earlier stages in patients with frequent exacerbation. However further and more long-term assessments are required.

Efficacy of budesonide in collagenous colitis Evaluation of: Miehlke S, Madisch A, Kupcinskas L, et al. Budesonide is more effective than mesalamine or placebo in short-term treatment of collagenous colitis. Gastroenterology 2014;146(5):1222-1230 e1222.

INTRODUCTION: Collagenous colitis (CC) is a less common colonic disease with variable prevalence and undulating course. Among the available therapies, budesonide was demonstrated to induce a rapid and sustained remission in many cases, but little is known about the comparative efficacy of other treatments, such as mesalamine. AREAS COVERED: Evaluation of a randomized study assessing the efficacy and safety of budesonide over mesalamine in patients with CC. EXPERT OPINION: Data from the study showed that budesonide was significantly superior to placebo and to mesalamine and further supports the recommendation of the current guidelines on the use of budesonide in CC. However, other forms of mesalamine may further be evaluated for this disease.

Health status during hospitalisations for chronic obstructive pulmonary disease exacerbations: the validity of the Clinical COPD Questionnaire.

Hospitalisations for chronic obstructive pulmonary disease (COPD) exacerbations are characterised by a significant worsening of the respiratory symptoms which can impair the health status (HS). However little is known on the HS behaviour during such events. Prospective study evaluating the validity of the Clinical COPD Questionnaire (CCQ) as a HS measure in hospitalisations for COPD exacerbations. The CCQ total score (CCQ-T) correlated with EQ-VAS (-0.51, p < 0.0001), was able to discriminate between longer and shorter duration hospitalisation (CCQ-T 3.83 vs 3.03, respectively p = 0.001), had a Cronbach-α of 0.86, and improved significantly over the hospitalisation period (CCQ-T on day 7 of hospitalisation 2.55 vs 3.77 at baseline, p < 0.0001). CCQ is an excellent tool for the assessment of the HS dynamics in hospitalisations for COPD exacerbations.

Nintedanib (BIBF 1120) for IPF: a tomorrow therapy?

Idiopathic pulmonary fibrosis is a rare, life threatening disease characterized by an anarchic fibrogenesis, limited survival and few therapeutic options. Its pathogenesis is complex and involves the interaction among various pathways driven by proinflammatory/profibrogenetic mediators such as platelet -derived growth factor, vascular endothelial growth factor or basic fibroblast growth factor. Given their prominent pathogenic roles in this disease such growth factor might be suitable therapeutic targets.In fact, the existing preclinical and clinical data demonstrated that their therapeutic inhibition results in a delayed progression of the pulmonary fibrosis and in the improvement of the disease outcome. BIBF 1120 is a potent triple blocker of the receptors of these growth factors which is currently evaluated as a potential therapy in the idiopathic pulmonary fibrosis. This review discusses the existing data supporting its potential use in this disease.

Discontinued drugs 2011: pulmonary, allergy, gastrointestinal and arthritis.

This is the annual perspective paper on the discontinued drugs in the field of pulmonary allergy, gastrointestinal, and arthritis conditions. It is part of series of papers discussing drugs discontinued from clinical development in the previous year and presented according to therapeutic indication. Specifically, this paper presents the 23 compounds developed for various inflammatory conditions and 10 pulmonary drugs which were discontinued in 2011. Information for this perspective was derived from a search of the Pharmaprojects database for drugs discontinued after reaching Phase-I - III clinical trials.

Roflumilast as add-on therapy to conventional inhalers in COPD: a cost-effectiveness analysis.

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory disease that is mainly linked to smoking and is associated with significant medical and economic burdens. For example, in the USA the estimated direct costs are US$29.5 billion, whereas at the EU level these costs are estimated to amount to approximately 56% of the costs related to respiratory diseases. COPD is characterized by chronic respiratory symptoms such as dyspnea and productive cough, which are progressive and further worsen during exacerbation of the disease. It is also associated with an abnormal lung function decline and with an increasing rate of exacerbations, the latter being responsible for most of the related direct costs. The existing inhaled therapies such as long-acting anticholinergics, long-acting ß2 agonists and inhaled corticosteroids are not always able to improve the disease outcome, and therefore other more effective therapies are needed; roflumilast is a recent example of such a therapy, being authorized for use in patients with severe and very severe COPD (i.e., with a forced expiratory volume in 1 s of <50% predicted) based on its ability to significantly reduce the exacerbation rate and the severity of respiratory symptoms.

Varenicline for smoking cessation intervention in chronic obstructive pulmonary disease.

INTRODUCTION: In smoking-related chronic obstructive pulmonary disease (COPD), smoking cessation was previously demonstrated to reduce lung function decline and disease morbidity if it resulted in a sustained tobacco abstinence. Varenicline is a newer pharmacologic therapeutic agent able to reduce withdrawal symptoms in smokers, and this makes it particularly valuable in inducing abstinence in patients with significant addiction. AREAS COVERED: This paper discusses the results of a randomized, placebo-controlled study evaluating the effects of a smoking cessation intervention including varenicline in patients with COPD. EXPERT OPINION: Varenicline can be an appropriate aid to maintaining smoking abstinence in patients with COPD and heavier nicotine addiction, and the documentation of the long-term effects of a smoking cessation intervention that includes this pharmacologic therapeutic agent is necessary.

Health status and chronic obstructive pulmonary disease severity.

Chronic obstructive pulmonary disease is a chronic disease in which health status can be measured with both generic and disease-specific questionnaires. These tools are able to evaluate improvements in daily functioning owing to various therapeutic methods and, despite a rather poor correlation with lung function, are able to correlate to the disease severity. In chronic obstructive pulmonary disease, this correlation between health status and disease severity has been demonstrated in many studies and the analysis discussed in this article adds further similar information in support of this statement.

Discontinued drugs 2010: rheumatology, allergy and dermatology, pulmonary.

This is the annual perspective paper on the discontinued drugs in the field of pulmonary disease allergy, rheumatology, and dermatology. It is part of series of papers discussing drugs dropped from clinical development in the previous year and presented according to therapeutic indication. Specifically, this paper presents the four rheumatology and dermatology, four pulmonary and three allergy drugs discontinued in 2010. Information for this perspective was derived from a search of the Pharmaprojects database for drugs discontinued after reaching Phase I - III clinical trials.

Predictors of depression in chronic obstructive pulmonary disease patients.

Evaluation of: Hanania NA, Mullerova H, Locantore NW et al. Determinants of depression in the ECLIPSE chronic obstructive pulmonary disease cohort. Am. J. Respir. Crit. Care Med. 183(5), 604-611 (2011). Chronic obstructive pulmonary disease (COPD) is a disease related to smoking and to other inhaled noxious agents, which initially is confined to the respiratory apparatus and subsequently becomes systemic, due to development of comorbid conditions such as systemic inflammation and depression. The latter is more frequently detected in patients with COPD than in the general population and is targeted therapeutically with various interventions which are part of pulmonary rehabilitation programs. Hanania et al. analyzed the determinants of depression in a cohort of COPD patients and found that the strongest predictor was health-related quality of life. A similar analysis performed on the COPD disease subset with highest incidence of depression would probably offer more relevant information on this topic.

Inhaled gentamicin in non-cystic fibrosis bronchiectasis: effects of long-term therapy.

Bronchiectasis is a disease state defined by irreducible dilations of the airways. If they occur in diseases other than cystic fibrosis they are termed non-CF bronchiectasis. The common denominator is the increased risk of recurrent infections with bacteria, such as Staphylococcus aureus or Pseudomonas aeruginosa. Such infections are difficult to eradicate with systemic antibiotics because the structural abnormalities in the bronchial wall reduce their bactericidal effect at this level. An alternative to systemic antibiotics might be represented by inhaled formulations, which can be given in much lower doses and can be more effective. Previous studies demonstrated that inhaled gentamicin can reduce bacterial load and local infection in both cystic fibrosis and non-CF bronchiectasis. The study discussed in this paper demonstrates that long-term therapy with inhaled gentamicin can eradicate the infection or reduce the bacterial load, decrease the risk of subsequent infections and improve the quality of life in patients with non-CF bronchiectasis with a minimal risk of side effects.

Targeting the Toll-like receptor 7 pathway in asthma: a potential immunomodulatory approach?

In allergic airways, as in asthma, inflammation and impaired functioning of toll-like receptor 7 (TLR7) has been found. The augmentation of this receptor with agonist compounds resulted in bronchodilation and a switch of the T(H)2 inflammatory pattern, specific for allergic conditions, to T(H)1 inflammation, characterised by an increased production of interferon-γ. This was a preclinical study evaluating the effects of two TLR7 agonists, imiquimod and resiquimod, on the isolated guinea pig trachea. The TLR7-related downstream signalling pathways were also assessed. Both TLR7 agonists were shown to reduce serotonin-induced bronchoconstriction, which is possibly exerted via the p38MAPK and NF-κB pathways. Therapeutic targeting of TLR7 with specific agonists might represent a promising immunomodulatory approach in asthma, especially if systemic exposure is minimised with inhaled formulations.

Pitrakinra, a dual IL-4/IL-13 antagonist for the potential treatment of asthma and eczema.

In asthma, airway inflammation is driven by Th2-related cytokines, such as IL-4, IL-5 and IL-13. IL-4 and IL-13, in particular, have a major role in the development of airway hyperresponsiveness, allergen-specific IgE synthesis and airway remodeling because of their synergistic effects induced by binding to the IL-4Rα subunit. Pitrakinra (AER-001, BAY-16-9996), being developed by Aerovance, under license from Bayer, for the potential treatment of asthma and eczema, is an IL-4 mutein, which binds to the IL-4Rα subunit and prevents the inflammation induced by IL-4 and IL-13. Pitrakinra demonstrated a potent inhibitory activity on IL-4/IL-13-mediated proliferative effects in vitro and reduced allergen-induced inflammation in animal models of asthma and skin inflammation. In phase I and II clinical trials in patients with asthma, subcutaneous and inhaled (as dry powder or nebulized) formulations of pitrakinra reduced airway inflammation, with superior effects observed with inhaled formulations. At the time of publication, a phase II clinical trial with the dry powder formulation of pitrakinra was ongoing in patients with asthma. Subcutaneous pitrakinra demonstrated preliminary efficacy results in patients with atopic eczema in a phase II clinical trial and a PEGylated variant of subcutaneous pitrakinra is being investigated for this indication. Further studies are warranted to allow a better therapeutic positioning and a more detailed characterization of the efficacy and safety of pitrakinra in asthma and atopic eczema.

Mogamulizumab, a humanized mAb against C-C chemokine receptor 4 for the potential treatment of T-cell lymphomas and asthma.

Mogamulizumab (KW-0761; AMG-761), under development by Kyowa Hakko Kirin and Amgen, is a defucosylated humanized IgG1 mAb against C-C chemokine receptor 4 (CCR4) for the potential intravenous treatment of T-cell lymphomas and asthma. Chemokines and their receptors are signaling molecules constitutively responsible for lymphocyte and neutrophil chemotaxis, which can also be involved in pathogenic mechanisms of various diseases. In particular, CCR4 has been demonstrated to play a major role in adult T-cell leukemia/lymphoma (ATL), in which it is a marker of poor prognosis. Consequently, CCR4 blockade might have therapeutic potential in treating ATL, a disease that is most often aggressive in course, and for which existing therapies are not always effective. Mogamulizumab reduced tumor load via enhanced antibody-dependent cell cytotoxicity in preclinical studies and demonstrated promising efficacy in early clinical trials in patients with ATL. In addition, CCR4 also has a role in maintaining T-helper cell type 2 airways inflammation in asthma, and Amgen have acquired the rights to develop mogamulizumab for this indication and other non-oncology indications; however, at the time of publication, no data were available from Amgen's investigations. This is a review on the potential use of mogamulizumab for the treatment of T-cell lymphomas and asthma, with specific emphasis on the treatment of ATL.

Pitrakinra for asthma.

IMPORTANCE OF THE FIELD: In asthma IL-4 and IL-13 have been demonstrated to play major pathogenic roles and therefore their blockade would potentially represent a plausible therapeutic approach. AREAS COVERED IN THIS REVIEW: Pitrakinra is a dual IL-4/IL-13 inhibitor currently under development for asthma and the existing preclinical and clinical data are discussed. WHAT THE READER WILL GAIN: Inhaled pitrakinra demonstrated a good anti-inflammatory potential and a good safety profile on a short-term basis but its place in asthma therapy is still to be found. TAKE HOME MESSAGE: Specific anticytokine therapies might in the near future reshape asthma therapy.

Daclizumab: a potential asthma therapy?

Airways inflammation in asthma is triggered and maintained by CD4+ (Th2) cells which are activated by IL-2 and stimulate the eosinophilic inflammation, IgE secretion and mucus hyperproduction. Current anti-inflammatory therapies include inhaled corticosteroids, and leukotriene modifiers but they are not universally effective. IL-2 pathway inhibition might represent a potent anti-inflammatory therapy in asthma given the cytokine early role in the asthma complex inflammatory cascade and daclizumab which is a IL-2R blocker currently used as an immunsupressor in organ transplantation might be a potential asthma therapy. This is review on the pathogenic role of IL-2, on the therapeutic potential of daclizumab and on its related patents.