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.

Beneficial Influence of Exendin-4 on Specific Organs and Mechanisms Favourable for the Elderly with Concomitant Obstructive Lung Diseases.

Exendin-4 (Ex-4), better known in its synthetic form and used clinically as exenatide, currently applied in the treatment of diabetes, induces a beneficial impact on nerve cells, and shows promising effects in obstructive lung diseases. At an advanced age, the development of the neurodegenerative process of brain tissue is masked by numerous concomitant diseases. The initial latent phase of neurodegenerative disease results in occurrence of manifestations at an advanced stage. To protect the brain and to simultaneously ensure proper treatment of common coexisting conditions in late life, such as diabetes, chronic obstructive pulmonary disease, or asthma, a pleiotropic medication should be chosen. Molecular mechanisms of Ex-4 exert neuroprotective effects or lead to secondary neurogenesis. Additionally, Ex-4 plays an important role in anti-inflammatory actions which are necessary both in the case of asthma and Parkinson's disease. Specific receptors in the lungs also reduce the secretion of surfactants, which decreases the risk of exacerbation in chronic obstructive lung disease. In a great number of patients suffering from diabetes, asthma, or chronic lung disease, there is a great potential for both treatment of the main condition and protection against brain neurodegeneration.

New insights into the regulation of TGF-ß/Smad and MPK signaling pathway gene expressions by nasal allergen and methacholine challenge test in asthma.

Background: Asthma is a heterogeneous chronic inflammatory disease of the bronchi, the course of which is significantly influenced by extrinsic factors (specific and non-specific). Methods: The aim of this study was to evaluate the effect of these factors represented by nasal allergen challenge (specific factors) and methacholine challenge test (non-specific) on changes in mRNA expression of genes encoding the TGF-ß (TGF-ß1 and TGF-ß3)‒Smad (mitogen-activated protein kinase 1/3 [MPK1/3], Smad1/3/6/7) signaling pathway in asthmatic patients. Results: Seventy-five subjects were included in the study, of whom 27 were applied an intranasal allergen provocation and 48 a methacholine provocation. There were 9 men and 18 women in the intranasal provocation group, and 17 men and 31 women in the methacholine test group. We found that both examined the types of challenges contributed to changes in the relative expression of genes of the TGF-ß (TGF-ß1 and TGF-ß3)‒Smad (MPK1/3, Smad1/3/6/7) signaling pathway in asthmatic patients. A decrease was noted for MAPK1, MAPK3, Smad3, Smad6, and Smad7 genes and an increase of up to 2.5 times for TGF-ß1 gene. Conclusions: Our experiment allows us to conclude that the change in the mRNA expression of the TGF-ß1-MPK1/3 and Smad3/6/7 genes occurs after an intranasal allergen and bronchial methacholine challenge.

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.

Prevalence of Chronic Polypharmacy in Community-Dwelling Elderly People in Poland: Analysis of National Real-World Database Helps to Identify High Risk Group.

Introduction: Multimorbidity often comes with age, making elderly people particularly prone to polypharmacy. Polypharmacy, in turn, is a risk factor for adverse drug reactions, drug-drug interactions, non-adherence to medication, negative health outcomes, and increased healthcare services utilization. The longer the exposure to polypharmacy is, the higher the risk of these consequences is. Therefore, a detailed assessment of the prevalence and drivers of chronic polypharmacy in the elderly is particularly important. Aim of study: To find out the prevalence of chronic polypharmacy in the elderly population of Poland, and to characterize the subgroup with the highest risk of this problem, using real-world data. Methodology: A retrospective analysis of data on dispensation and healthcare services utilization held by the national payer organization for the year 2018. Chronic polypharmacy was defined as possession, as a result of dispensation, of five or more prescribed drugs within 80% of each of the consecutive 6 months. Results: Chronic polypharmacy was found in 554.1 thousand patients, i.e. in 19.1% of the national 65+ cohort. On average, those patients were 76 years old, and 49.3% of them were female. The vast majority (68.6%) continued their polypharmacy for the period of the whole year. There was a marked variation in geographical distribution of chronic polypharmacy with the highest value of 1.7 thousand per 100,000 inhabitants in the Lódz Voivodeship. Patients exposed to chronic polypharmacy filled prescriptions from 4.5±2.36 healthcare professionals. The average number of drugs they used was 8.3±3.84 DDD per patient per day. The most often prescribed drugs were Metformin, Atorvastatin and Pantoprazole. The average annual hospitalisation rate in those patients was 1.03±2.4. Conclusion: This study was the first of this kind involving a nationwide assessment of chronic polypharmacy in Polish elderly people. We found that this problem affected one fifth of Polish older adults and it remains stable due to its direct relation to chronic conditions. Thus, our results confirm that this phenomenon is highly important for the national health policy and requires relevant interventions. The planned introduction of pharmaceutical care in Poland is expected to help in solving the problem.

Prevalence and Age Structure of Polypharmacy in Poland: Results of the Analysis of the National Real-World Database of 38 Million Citizens.

Introduction: Polypharmacy is a risk factor for adverse health outcomes, higher use of medical services and additional costs. The problem has gained attention as a consequence of aging and related multimorbidity. Therefore, there is an urgent need to adopt effective interventions aimed at reducing its burden. In order to achieve this, in-depth understanding of the prevalence of polypharmacy is required. Of particular interest is, however, assessing prevalence of polypharmacy in various age groups, to reach the right target for these interventions. So far, only limited data on polypharmacy among non-elderly individuals have been available. Aim of study: To assess overall prevalence of polypharmacy in Poland as well as its distribution in various age groups using real-world data. Methodology: A retrospective analysis of complete dispensation data of national payer organization for the years 2018-2019. The analyzed dataset included data on dispensation of reimbursed drugs, and exclusively for 2019, also non-reimbursed drugs. Polypharmacy was defined as dispensation of ≥5 prescription medications within six months. Results: In the analyzed national cohort of 38 million Polish citizens, the prevalence of polypharmacy was found to be 11.7% in 2018 and 11.6% in 2019. With age, the prevalence of polypharmacy increased, reaching the value of 56.0% in those aged 80+ in 2018, and 55.0% in 2019. Altogether, among those aged 65+, the polypharmacy was present in 43.1% in 2018, and 42.1% in 2019. In the youngest group of citizens, i.e., among those aged below 20 years, polypharmacy was found in 0.9%, and 0.8% in 2018 and 2019, respectively. Prevalence of polypharmacy, calculated for 2019 according to dispensation of five or more reimbursed and non-reimbursed drugs for the whole Polish population, was 21.8% for January-June, and 22.4% for July-December 2019. Among those aged 65+, the relevant numbers were 62.3%, and 62.9%, respectively. Conclusion: This study, being the first nationwide assessment of polypharmacy in Poland, confirmed its high prevalence. We found polypharmacy present in over one fifth of Polish society. Peaking in the elderly, polypharmacy occurred in each age group. These results lay the foundations for future interventions focused on reducing the scope of this problem in Poland.

The predictive value of BOAH scale for screening obstructive sleep apnea in patients at a sleep clinic in Scotland.

OBJECTIVES: The study aimed to evaluate the diagnostic value of an original questionnaire for obstructive sleep apnea (OSA), the BOAH scale, and its ability to prioritize patients at high risk for OSA for polysomnography (PSG) examination. METHODS: The analysis included 273 patients referred to the Department of Sleep Medicine of the Royal Infirmary, Edinburgh, Scotland. The BOAH scale is comprised of 5 parameters: BMI (≥ 30 kg/m2 gives 1 point, ≥ 35 kg/m2 2 points), presence of witnessed apneas during sleep (1 point), patient age ≥ 50 years (1 point), and history of hypertension (1 point). Patients were divided into three study groups depending on OSA severity defined by the apnea-hypopnea index (AHI): at least mild (AHI ≥ 5), at least moderate (AHI ≥ 15), and severe (AHI ≥ 30) OSA based on polysomnography examination. RESULTS: In the group of patients with severe OSA, the best BOAH cutoff point was 4 points based upon the Youden index. With 4 points, the area under the receiver operating characteristic (ROC) curve was 0.778 (95% CI 0.721-0.834). Sensitivity and specificity were 57% and 89%, respectively, yielding a positive and negative predictive value of 75% and 78%, respectively, for diagnosis of severe OSAS in a patient sample with a pre-test probability for severe OSA at 37%. CONCLUSIONS: The BOAH scale in this group of Scottish patients performed comparably to other available questionnaires and scales while being shorter and simpler. The findings suggest that the BOAH scale should be considered as a useful instrument in OSA diagnosis and prioritization of high-risk patients for PSG examination.

Primary non-adherence to inhaled medications measured with e-prescription data from Poland.

BACKGROUND: Treatment adherence greatly influences the clinical outcomes in various fields of medicine, including management of asthma and COPD. With the recent implementation of a nationwide e-Health solutions in Poland, new and unique opportunities for studying primary non-adherence in asthma and COPD emerged. The aim was to study primary non-adherence to inhaled medications available in Poland indicated in asthma and/or COPD and analyse the impact of patients' demographics and inhalers' characteristics (dry powder inhalers (DPIs) vs metered dose inhalers (MDIs) and presence of a dosage counter) on primary non-adherence. METHODS: A retrospective analysis of all e-prescriptions issued in Poland in 2018 (n = 119,880) from the national e-prescription pilot framework. RESULTS: Primary non-adherence for inhalable medications reached 15.3%. It significantly differed among age groups-the lowest (10.8%) was in 75 + years-old patients, highest (18%) in 65-74 years-old patients. No gender differences in primary non-adherence were found. The highest non-adherence was observed for ICS + LABA combinations (18.86%). A significant difference was found between MDI and DPI inhalers and between inhalers with/without a dosage counter. CONCLUSIONS: Out of e-prescriptions for inhaled medications issued in 2018 in Poland, 15.3% were not redeemed. The degree of primary non-adherence was influenced by age, but not gender. Significant differences between MDIs and DPIs and between inhalers with/without a dosage counter were observed.

Mental Well-Being (Depression, Loneliness, Insomnia, Daily Life Fatigue) during COVID-19 Related Home-Confinement-A Study from Poland.

The COVID-19 pandemic is a great threat to both physical and mental health as it may lead to psychological stress connected with an economic crisis, threat of unemployment, or fear of losing family members. Emerging data shows that the general public may be vulnerable to the pandemic-related stress and experience frequently prevalent anxiety. A study involving 471 subjects (85.6% female) was conducted online during the COVID-19 pandemic. We used the following scales: Insomnia Severity Index (ISI), Beck Depression Inventory (BDI), Revised University of California, Los Angeles (R-UCLA) Loneliness Scale, and Daily Life Fatigue scale (DLF). Women had higher mean scores of depression, loneliness, and daily life fatigue and more often than males started exercising. Among people professionally active before the pandemic, there were more cases of increased alcohol consumption than among students. No differences in alcohol consumption patterns were found between genders. People living alone had higher scores of loneliness and daily life fatigue compared to those living with someone. Respondents who started taking any new drugs during COVID-19 home confinement had higher outcomes in all questionnaires. During home confinement, high scores of depression, insomnia, loneliness, and everyday fatigue were observed.

Biological Therapies of Severe Asthma and Their Possible Effects on Airway Remodeling.

Asthma is a chronic and heterogenic respiratory tract disorder with a high global prevalence. The underlying chronic inflammatory process and airway remodeling (AR) contribute to the symptomatology of the disease. The most severely ill asthma patients may now be treated using a variety of monoclonal antibodies aiming key inflammatory cytokines involved in asthma pathogenesis. Although clinical data shows much beneficial effects of biological therapies in terms of reduction of exacerbation rates, improvement of lung functions, asthma control and patients' quality of life, little is known on the effects of these monoclonal antibodies on AR-a key clinical trait of long-term asthma management. In this review, the authors summarize the data on the proven effects of monoclonal antibodies in asthma on AR. To date, in terms of reversing AR, the mostly studied was omalizumab. However, some studies also addressed this clinical issue in context of other severe asthma biological therapies (mepolizumab, benralizumab, tralokinumab). Still, data on effects of particular biological therapies on AR in severe asthma are incomplete and require further studies. According to the American Thoracic Society research recommendations, future research shall focus on AR in asthma and improve drugs targeting AR, including the available and future monoclonal antibodies.

Primary Non-Adherence to Antihistamines-Conclusions From E-Prescription Pilot Data in Poland.

BACKGROUND: In allergic conditions such as allergic rhinitis and urticaria, orally administered H1-antihistamines belong to first-line therapy and therefore, are widely prescribed. Due to the frequent, and often chronic, course of allergic diseases, adherence is of great importance. In 2018 a novel, nationwide e-prescription system was piloted in Poland, which allowed to analyze primary non-adherence to orally administered H1 antihistamines. OBJECTIVES: To assess the primary non-adherence to orally administered H1-antihistamines in Poland, defined as not redeeming the drug issued on a particular e-prescription within its validity period. METHODS: The study was based on all e-prescriptions issued in Poland in 2018, issued for 119.880 drugs. The analysis included nine major orally administered H1 antihistamines available in Poland. RESULTS: Out of 2280 analyzed e-prescriptions on orally administered antihistamines, 1803 (79.1%) of them were redeemed. Therefore, the level of primary non-adherence reached 21%. Among women it reached 19.9%, but it was not significantly lower than among men (23.4%, p=0.064). The highest non-adherence (31.3%) was observed in the age group 19-39, whilst the highest adherence rate (84.6%) was observed in those 75 years or older. The most frequently prescribed second-generation antihistamine was bilastine-596 e-prescriptions with 23.7% primary non-adherence. CONCLUSIONS: More than 1 out of 5 e-prescriptions on orally administered H1-antihistamines were not redeemed in Poland in 2018. Age, but not gender, significantly influenced the degree of primary non-adherence to these drugs. To authors knowledge, this is the first real-life study on primary non-adherence to H1-antihistamines in Poland and one of the very few on this subject worldwide.

Role of Platelet-Derived Growth Factor (PDGF) in Asthma as an Immunoregulatory Factor Mediating Airway Remodeling and Possible Pharmacological Target.

Asthma is a chronic and heterogenic disease of the respiratory system, one of the most common lung diseases worldwide. The underlying pathologies, which are chronic inflammatory process and airway remodeling (AR), are mediated by numerous cells and cytokines. Particularly interesting in this field is the platelet-derived growth factor (PDGF), one of the members of the human growth factor family. In this article, the authors analyze the available data on the role of PDGF in asthma in experimental models and in human research. PDGF is expressed in airway by various cells contributing to asthma pathogenesis-mast cells, eosinophils, and airway epithelial cells. Research confirms the thesis that this factor is also secreted by these cells in the course of asthma. The main effects of PDGF on bronchi are the proliferation of airway smooth muscle (ASM) cells, migration of ASM cells into the epithelium and enhanced collagen synthesis by lung fibroblasts. The importance of AR in asthma is well recognized and new therapies should also aim to manage it, possibly targeting PDGFRs. Further studies on new and already existing drugs, mediating the PDGF signaling and related to asthma are necessary. Several promising drugs from the tyrosine kinase inhibitors group, including nilotinib, imatinib masitinib, and sunitinib, are currently being clinically tested and other molecules are likely to emerge in this field.

The Prevalence of Selected Potential Drug-Drug Interactions of Analgesic Drugs and Possible Methods of Preventing Them: Lessons Learned From the Analysis of the Real-World National Database of 38 Million Citizens of Poland.

Introduction: Drug-drug interactions may lead to poor health outcomes, as well as increased costs and utilization of healthcare services. Unfortunately, real-world data continuously prove high prevalence of potential drug-drug interactions (pDDIs) worldwide. Among identified drivers, ageing, multimorbidity and polypharmacy play a very important role. With these factors being widespread, the need for implementation of strategies minimizing the burden of pDDIs becomes an urgency. This, however, requires a better understanding of the prevalence of pDDIs and the underlying causative factors. Aim of study: To assess the real-world prevalence of pDDIs and its characteristics in the general population of Poland, using analgesic drugs as a model, and to find out whether pDDIs are caused by prescribing coming from the very same prescribers (co-prescribing). Methods: A retrospective analysis of the 2018 dispensation data of the National Health Fund (NHF) - the only Polish public healthcare payer organization with nationwide coverage. We searched for selected pDDIs of non-steroidal anti-inflammatory drugs (NSAIDs) with antihypertensives, other NSAIDs (double use), oral glucocorticoids, oral anticoagulants, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and antiplatelet drugs; as well as opioides with SSRIs, SNRIs, gabapentinoids, and benzodiazepines. A pDDI was deemed present if two drugs standing in a possible conflict were dispensed within the same calendar month. Results: Out of 38.4 million citizens of Poland, 23.3 million were dispensed prescribed drugs reimbursed by NHF in 2018. In this cohort, we have identified 2,485,787 cases of analgesic drug pDDIs, corresponding with 6.47% of the Polish population. Out of these, the most prevalent pDDI was caused by "NSAIDs + antihypertensives" (1,583,575 cases, i.e., 4.12% of the Polish population), followed by "NSAIDs + NSAIDs" (538,640, 1.40%) and "NSAIDs + glucocorticoids" (213,504, 0.56%). The most persistent pDDIs among those studied were caused by "Opioids + Gabapentinoids" (2.19, 95%CI: 2.16-2.22 months). On average, 76.63% of all cases of pDDIs were caused by drugs prescribed by the very same prescribers. Conclusion: Based on high-quality, nationwide data, we have found a high prevalence of analgesic drugs-related pDDIs in Poland. Over ¾ of the identified pDDIs were caused by co-prescribing, i.e., prescriptions issued by the same prescribers. The significance of the problem, illustrated with our findings on analgesic drugs-related pDDIs in Poland, deserves much more scientific and policymaker attention.

Diagnostic challenges in interstitial lung diseases using the example of microscopic usual interstitial pneumonia image in a patient with the clinical hypothesis of idiopathic pulmonary fibrosis - a case report.

Idiopathic pulmonary fibrosis (IPF) is the most common of the idiopathic interstitial pneumonias. The high-resolution tomography (HRCT) is highly recommended among patients with suspected IPF. Usual interstitial pneumonia (UIP) is the histopathological and radiological pattern of IPF. IPF is diagnosed if the appropriate combination of HRCT patterns and histopathological patterns are present. CASE REPORT: The authors present a case of a 49-years-old woman who was hospitalised due to the detection of a focal lesion in the left lung in an X-ray examination. A CT scan of the chest with contrast revealed a solid infiltration of the same area. The histopathology from a transbronchial lung biopsy from this abnormality showed microscopic honeycomb, fibroblast fibrosis, macrophage clusters loaded with hemosiderin and widened bronchioles - an image suggesting Usual Interstitial Pneumonia (UIP). Following that, a HRCT showed considerable differences in the lung image compared to the previous CT examination - no polycyclic lesion in the left lung was detected and the fibrous changes decreased. The patient had substantial formal features of UIP from the histopathological examination from TBLB. Therefore, there was a clinicalradiological discrepancy in the histopathology report. After a multidisciplinary consultation by renowned experts in pulmonology, radiology and histopathology, regardless of the patient's diagnostic path, the primary cause of the disease could not be determined. The analysis of this case strongly suggests that the histopathological examination alone is not sufficient in the diagnosis of IPF.

Possible application of trefoil factor family peptides in gastroesophageal reflux and Barrett's esophagus.

Gastroesophageal reflux disease (GERD) is a chronic disorder of the digestive tract characterised mainly by a heartburn. Being one of the most common gastrointestinal diseases, the prevalence of GERD reaches up to 25.9% in Europe. Barrett's esophagus (BE) is an acquired condition characterized by the replacement of the normal stratified squamous epithelium with metaplastic columnar epithelium. BE is believed to develop mainly from chronic GERD and is the most important risk factor of esophageal adenocarcinoma. Despite the availability of drugs such as proton pomp inhibitors and antacids, GERD is still a burden to local economy and impairs health-related quality of life in patients. Also, the endoscopic surveillance in patients with BE is burdensome and expensive what drives the need for biomarker of intestinal metaplasia and dysplasia. Trefoil factor family (TFF), consisting of TFF1, TFF2 and TFF3 peptides is gaining more and more attention due to its unique biochemical features and numerous functions. In this review the role of TFF1, TFF2 and TFF3 as potential treatment option and/or biomarker in the upper GI tract is discussed with particular focus on GERD and BE.