Clinical profiles of patients referred for biological therapy and major limitations in the qualification paths in a specialist asthma centre.

Introduction: Despite the proven efficacy of biologics in the treatment of severe asthma, still a limited number of patients are included in the Polish therapeutic programme. Aim: To identify major limitations in the qualification paths and predominant reasons leading to exclusion from available biologic treatments. The clinical profiles of patients referred for biologics were also examined. Material and methods: Data on demographic characteristics, clinical profile, biomarkers, and medical history from one visit of patients that had been referred for qualification for biologics in 2018/2019 to the Barlicki Hospital (Poland) were collected. A comparison between eligible and ineligible patients was made. Results: Within 2 years, only 116 patients had been referred to the biologic therapy of whom 93 (80%) had been suitable for the biologic programme. Criteria for the omalizumab programme included major limitations such as: frequent use of oral corticosteroids in the past, and serum total-IgE 30-1000 IU/ml, and for mepolizumab were blood eosinophil count (EOScount) > 350/µl and spirometric criterion. Ineligible patients had a significantly lower EOScount and better lung function than eligible individuals despite no significant differences in the number of exacerbations or quality of life between groups. A high percentage of ineligible patients had been referred to re-verify the diagnosis of severe asthma. Conclusions: Potential limitations for biologic therapy include restrictive criteria limiting the group of patients to the most severe cases and referring patients with difficult-to-treat asthma without a differential diagnosis. Low awareness and knowledge among physicians who often are not familiar with qualification criteria require extensive education.

Monoclonal antibodies in the management of asthma: Dead ends, current status and future perspectives.

Patients with moderate-to-severe asthma may now be treated using a variety of monoclonal antibodies that target key inflammatory cytokines involved in disease pathogenesis. Existing clinical data on anti-IgE, anti-IL-5 and other immunological pathways indicate these therapies to offer reduced exacerbation rates, improved lung function, greater asthma control and better quality of life. However, as several patients still do not achieve satisfactory clinical response with the antibodies available, many more biologics, aiming different immunological pathways, are under evaluation. This review summarizes recent data on existing and potential monoclonal antibodies in asthma. Recent advances have resulted in the registration of a new antibody targeting TSLP (tezepelumab), with others being under development. Some of the researched monoclonal antibodies (e.g. anti-IL-13 tralokinumab and lebrikizumab or anti-IL-17A secukinumab) have shown optimistic results in preliminary research; however, these have been discontinued in asthma clinical research. In addition, as available monoclonal antibody treatments have shown little benefit among patients with T2-low asthma, research continues in this area, with several antibodies in development. This article summarizes the available pre-clinical and clinical data on new and emerging drugs for treating severe asthma, discusses discontinued treatments and outlines future directions in this area.

Improving the risk-to-benefit ratio of inhaled corticosteroids through delivery and dose: current progress and future directions.

INTRODUCTION: Inhaled corticosteroids (ICS) are known to increase the risk of systemic and local adverse effects, especially with high doses and long-term use. Hence, considerable resources are invested to improve pharmacokinetic/pharmacodynamic (PK/PD) properties of ICS, effective delivery systems and novel combination therapies to enhance the risk-to-benefit ratio of ICS. AREAS COVERED: There is an unmet need for new solutions to achieve optimal clinical outcomes with minimal dose of ICS. This paper gives an overview of novel treatment strategies regarding the safety of ICS therapy on the basis of the three most recent molecules introduced to our everyday clinical practice - ciclesonide, mometasone furoate, and fluticasone furoate. Advances in aerosol devices and new areas of inhalation therapy are also discussed. EXPERT OPINION: Current progress in improving the risk-to-benefit ratio of ICS through dose and delivery probably established pathways for further developments. This applies both to the improvement of the PK/PD properties of ICS molecules but also includes technical aspects that lead to simplified applicability of the device with simultaneous optimal drug deposition in the lungs. Indubitably, the future of medicine lies not only in the development of new molecules but also in technology and digital revolution.

Generalized emphysema and chronic obstructive pulmonary disease in a farmer, non-smoker - the more we seek, the more we find.

Although alpha-1 antitrypsin (A1AT) deficiency represents one of the most common genetically conditioned diseases in the population of Caucasian adult individuals, it is rarely diagnosed. Alpha-1 antitrypsin is an important component of the anti-proteolytic protection in the lungs. Individuals affected by the protein deficiency are exposed to a higher risk of developing chronic obstructive pulmonary disease (COPD), emphysema or liver diseases. A CASE REPORT: A 52-year-old farmer, non-smoker, spraying orchards since the age of 15 years, was admitted to the Department with dyspnea at rest and productive cough. He had a medical history of COPD, congestive heart failure, generalized emphysema of ten years' duration On admission the patient's general condition was satisfactory (fair). Physical examination showed symmetric expiratory wheezing over the upper and lower fields of the lungs with loss of vesicular murmur in the lower fields. Spirometry revealed a severe chronic bronchial obstruction, and an arterial blood gas test showed hypoxemia. Laboratory tests demonstrated an increased concentration of inflammatory markers. High resolution computed tomography (HRCT) of the chest showed evidence of generalized emphysema, bronchiectasis and exacerbation of peribronchial inflammatory changes. Intensive anti-inflammatory, bronchodilator treatment and antibiotic therapy were implemented, which resulted in an optimal improvement of the patient's condition. Based on the whole clinical picture A1AT deficiency was suspected. Alpha-1-antitrypsin deficiency, MZ phenotype, with 65 mg/dl concentration was diagnosed. CONCLUSIONS: Diagnostic tests for alpha-1 antitrypsin deficiency should always be considered in patients with emphysema or symptomatic COPD identified at an early age. In the described case the period between occurrence of clinical signs and establishing the diagnosis was ten years, which proves that there is a strong need to spread knowledge on A1AT among medical professionals. Otherwise, most of the patients will lose their chance of modifying their lifestyle or receiving proper treatment that could prevent the progression of changes in the lungs.

Neprilysin inhibitors as a new approach in the treatment of right heart failure in the course of chronic obstructive pulmonary disease.

The aim of the study was to find out scientific evidence on the possible use of the combined angiotensin II receptor antagonist and neprilysin inhibitors (ARNI) in patients with right heart failure (RHF) in the course of chronic obstructive pulmonary disease (COPD). It has been proven that a lack of neprilysin or its reduced expression in hypoxia leads to exacerbation of pulmonary arterial remodelling (PAR) or pulmonary hypertension (PH) in the mechanism related to the platelet-derived growth factor (PDGF) resulting in the proliferation and migration of pulmonary artery smooth muscle cells and endothelial-to-mesenchymal transition. Such action in the course of COPD can lead to RHF, which would signify noxious effect of this group of drugs. However, the inhibition of neprilysin also inhibits natriuretic peptide metabolism. The representative of this group - brain natriuretic peptide (BNP) - acts as a vasodilator and also exerts an anti-proliferative activity through the cGMP-dependent protein kinase G pathway. Additionally, it causes bronchodilation by inducing the release of acetylcholine from bronchial epithelial cells. This suggests that natriuretic peptides may appear to be a potential treatment agent in patients with cardiac complications and COPD. Their effects associated with the immunosuppression capacity by reducing the release of inflammatory mediators - IL-6, IL-1ß, and TNF-α can bring benefits to patients with acute lung injury caused by pulmonary inflammation during COPD exacerbations. Considering the potentially positive effect of natriuretic peptides in this group of patients, further research is required in this area, which can provide strong scientific data demonstrating the need for introducing ARNI drugs to the treatment of patients with COPD.