A Randomized, Double-blind, Phase III Study Assessing Clinical Similarity of SB17 (Proposed Ustekinumab Biosimilar) to Reference Ustekinumab in Subjects with Moderate to Severe Plaque Psoriasis.

BACKGROUND: Ustekinumab is a safe and effective treatment for moderate-to-severe psoriasis. OBJECTIVES: To compare efficacy, safety, pharmacokinetics (PK), and immunogenicity of the proposed ustekinumab biosimilar SB17 with reference ustekinumab (UST) in subjects with moderate to severe plaque psoriasis. METHODS: In this randomized double-blind study, subjects were randomized to receive 45 mg of SB17 or UST subcutaneously at Week 0, 4, and every 12 weeks. The primary endpoint was the percent change from baseline in Psoriasis Area and Severity Index (PASI) at Week 12 with an equivalence margin of [-15%, 15%]. Other secondary efficacy, safety, PK, and immunogenicity endpoints were measured through Week 28. RESULTS: 249 subjects were randomized to SB17, 254 to UST. Adjusted difference of PASI change from baseline at Week 12 of -0.6% (95% confidence interval [CI; -3.780, 2.579]) was within the equivalence margin. Physician's Global Assessment (PGA) and Dermatology Life Quality Index (DLQI) were also comparable. Overall treatment-emergent adverse events (TEAEs) were comparable (SB17: 48.2%, UST: 48.8%). The overall incidence of anti-drug antibodies (ADAs) up to Week 28 was 13.3% with SB17 and 39.4% with UST. LIMITATIONS: Data were only through Week 28. CONCLUSION: SB17 was clinically biosimilar to UST up to Week 28.

Phase 2b randomized trial of OX40 inhibitor telazorlimab for moderate-to-severe atopic dermatitis.

Background: Telazorlimab is a humanized anti-OX40 monoclonal antibody being studied for treatment of T-cell-mediated diseases. Objective: This randomized, placebo-controlled, phase 2b dose-range finding study investigated efficacy, safety, pharmacokinetics, and immunogenicity of telazorlimab in subjects with atopic dermatitis. Methods: In this 2-part study (NCT03568162), adults (≥18 years) with moderate-to-severe disease were randomized to various regimens of subcutaneous telazorlimab or placebo for 16 weeks' blinded treatment, followed by 38 weeks' open-label treatment and 12 weeks' drug-free follow-up. Telazorlimab treatment groups (following a loading dose) in part 1 were 300 mg every 2 weeks; 300 mg every 4 weeks; or 75 mg every 4 weeks. Part 2 evaluated telazorlimab 600 mg every 2 weeks. The primary end point was percentage change from baseline in Eczema Area and Severity Index (EASI) at week 16. Safety assessments included incidence of treatment-emergent adverse events. Results: The study randomized 313 subjects in part 1 and 149 in part 2. At 16 weeks, the least squares mean percentage change from baseline in EASI was significantly greater in subjects receiving telazorlimab 300 mg every 2 weeks (part 1) and 600 mg every 2 weeks (part 2) versus placebo (-54.4% vs -34.2% for part 1 and -59.0% vs -41.8% for part 2, P = .008 for both). Telazorlimab was well tolerated, with similar distribution of adverse events between telazorlimab- and placebo-treated subjects in both part 1 and part 2. Conclusion: Telazorlimab, administered subcutaneously at 300 mg every 2 weeks or 600 mg every 2 weeks following a loading dose, was well tolerated and induced significant and progressive clinical improvement in adults with moderate-to-severe atopic dermatitis.

Safety and Tolerability of Bilastine 0.6% Ophthalmic Solution: An 8-Weeks Phase III Study.

Purpose: The objective of this study was to assess the safety and tolerability of preservative-free bilastine 0.6% ophthalmic solution after 8 weeks of once-daily administration in patients with allergic conjunctivitis (AC). Patients and Methods: Multi-center, international, randomized, double blind, placebo-controlled, parallel-group, phase III study of adult patients with seasonal or perennial AC. The study was conducted in 26 centers of 5 European countries. Duration of daily treatment with bilastine 0.6% ophthalmic solution or placebo was 8 weeks. Safety was evaluated by analyzing incidence of ocular treatment-emergent adverse events (TEAEs); additionally, and as secondary parameters, ocular tolerability was assessed, in addition efficacy was also assessed by the average daily total eye symptoms score (TESS). Results: A total of 333 randomized patients with AC were included (bilastine, N=218; placebo, N=115). Mean (SD) age of the patients was 39.9 (13.7) and were 63.7% female. Overall, the percentage of ocular related TEAEs was low, and the percentage of patients with ocular related TEAEs was lower in the bilastine ophthalmic solution group (2.8%) than in the placebo group (4.3%). No severe TEAEs were reported. The ocular symptoms and TESS improved during the trial in both treatment groups. Statistically significant treatment differences were observed at Week 8 for the TESS and all individual ocular symptoms, being significantly better in the bilastine ophthalmic solution group than in placebo group. Conclusion: Bilastine 0.6% ophthalmic solution revealed no safety concerns in patients with AC after 8 weeks of once-daily administration. Bilastine was effective in reducing ocular symptoms associated with AC in response to both seasonal and perennial allergens.

Efficacy, Safety and Immunogenicity of AVT02 Versus Originator Adalimumab in Subjects with Moderate to Severe Chronic Plaque Psoriasis: A Multicentre, Double-Blind, Randomised, Parallel Group, Active Control, Phase III Study.

BACKGROUND: AVT02 (adalimumab) is a proposed biosimilar to Humira®. AVT02 is produced at a 100 mg/mL concentration with a citrate-free formulation. OBJECTIVES: The aim of this study was to compare the efficacy, safety and immunogenicity of AVT02 versus Humira® in subjects with moderate to severe chronic plaque psoriasis. METHODS: This double-blind, randomised, parallel group, active control study of adult subjects compared (at a 1:1 ratio) AVT02 with originator adalimumab 80 mg subcutaneously in Week 1, then 40 mg every other week. At Week 16, subjects who had received originator adalimumab were re-randomised at a 1:1 ratio to continue receiving originator adalimumab, or to switch to AVT02, every other week until Week 48, with final efficacy endpoint at Week 50. Subjects who initially received AVT02 continued to receive AVT02 from Week 16 to Week 48. The primary endpoint was percentage improvement in Psoriasis Area and Severity Index (PASI) score at Week 16. Secondary efficacy endpoints included percentage improvement in PASI score at additional timepoints, change from baseline in Dermatology Life Quality Index (DLQI) score and number and percentage of subjects achieving static Physician's Global Assessment (sPGA) responses of 'clear' or 'almost clear'. Additional secondary endpoints included comparison of adverse event profiles, anti-drug antibodies and neutralising antibodies, and serum trough levels of adalimumab at steady state. RESULTS: A total of 413 subjects were randomised (205 to AVT02 and 208 to originator). The percentage improvement in PASI score at Week 16 was 91.6% for AVT02-treated subjects and 89.6% for originator adalimumab. The 90% confidence intervals for the primary endpoint were within the pre-defined equivalence margin of ±10% (90% CI - 0.76 to 5.29; 95% CI - 1.34 to 5.88), and a comparable pattern for DLQI score (11.4-point and 10.6-point improvement in AVT02-treated and originator adalimumab-treated groups, respectively) and sPGA (90.5% in both groups achieving 'clear' or 'almost clear') at Week 16 supported the assessment. Efficacy persisted through Week 50 of the study in all treatment groups, including those who switched from originator adalimumab to AVT02, for percent improvement in PASI score, quality-of-life assessment and sPGA. The safety, tolerability and immunogenicity profiles between AVT02 and originator adalimumab were similar at Week 16, and this persisted in the switched and continued groups through Week 50. CONCLUSION: Objective and subjective measures of efficacy supported the evaluation of biosimilarity between AVT02 and originator adalimumab at Week 16 and until Week 50, in switched and continued treatment groups. AVT02 was safe and well tolerated, with a safety and immunogenicity profile similar to that observed in originator adalimumab with no clinically meaningful difference between the two. CLINICAL TRIAL REGISTRATION: EudraCT: 2017-003367-35; ClinicalTrials.gov: NCT03849404.

Efficacy and safety of bilastine in reducing pruritus in patients with chronic spontaneous urticaria and other skin diseases: an exploratory study.

Purpose: To evaluate the efficacy/safety of bilastine in pruritus relief in patients with chronic spontaneous urticaria (CSU) or other pruritic skin diseases.Methods: In this multicenter, open-label, exploratory study (EudraCT No.: 2016-001505-17), 115 adults with CSU (n = 34), eczema/dermatitis (n = 30), prurigo (n = 25) or cutaneous pruritus (n = 26), received bilastine 20 mg once daily for 8 weeks, or in non-responder patients (<30% improvement in pruritus score at week 2), 40 mg/day from week 2.Results: The mean change in weekly pruritus severity score from baseline to week 8 (primary endpoint) was reduced with bilastine (overall and by disease group); overall, percentage and absolute reductions were 71.16% and 1.63 points, respectively (p < .001). Updosed non-responders (n = 31) had improved weekly pruritus severity scores from baseline to week 8; percentage and absolute reductions were 49.08% and 1.13 points, respectively (p < .001). Bilastine improved the Dermatology Life Quality Index at weeks 4 and 8 (p < .001) in all disease groups, and the 7-day Urticaria Activity Score in CSU patients (p < .001). Bilastine was well tolerated.Conclusions: Bilastine relieved pruritus associated with urticaria and other skin diseases, with a very good safety profile.

Phase 2B randomized study of nemolizumab in adults with moderate-to-severe atopic dermatitis and severe pruritus.

BACKGROUND: Nemolizumab targets the IL-31 receptor α subunit involved in atopic dermatitis (AD) pathogenesis. OBJECTIVE: We sought to evaluate a new dosing strategy of nemolizumab in patients with AD. METHODS: We performed a 24-week, randomized, double-blind, multicenter study of nemolizumab (10, 30, and 90 mg) subcutaneous injections every 4 weeks versus placebo, with topical corticosteroids in adults with moderate-to-severe AD, severe pruritus, and inadequate control with topical treatment (n = 226). The Eczema Area and Severity Index (EASI), the peak pruritus (PP) numeric rating scale (NRS), and the Investigator's Global Assessment (IGA) were assessed. Standard safety assessments were performed. RESULTS: Nemolizumab improved EASI, IGA, and/or NRS-itch scores, with the 30-mg dose being most effective. Nemolizumab (30 mg) reduced EASI scores versus placebo at week 24 (-68.8% vs -52.1%, P = .016); significant differences were observed by week 8 (P ≤ .01). With significant improvement (P = .028) as early as week 4, IGA 0/1 rates were higher for 30 mg of nemolizumab versus placebo at week 16 (33.3% vs 12.3%, P = .008) but not week 24 because of an increased placebo/topical corticosteroid effect (36.8% vs 21.1%, P = .06). PP-NRS scores were improved for 30 mg of nemolizumab versus placebo at week 16 (-68.6% vs -34.3%, P < .0001) and week 24 (-67.3% vs -35.8%, P < .0001), with a difference by week 1 (P < .001). NRS response rates (≥4-point decrease) were greater for 30 mg of nemolizumab versus placebo at week 16 (P ≤ .001) and week 24 (P ≤ .01). Nemolizumab was safe and well tolerated. The most common adverse events were nasopharyngitis and upper respiratory tract infection. CONCLUSIONS: Nemolizumab resulted in rapid and sustained improvements in cutaneous signs of inflammation and pruritus in patients with AD, with maximal efficacy observed at 30 mg. Nemolizumab had an acceptable safety profile.

Nemolizumab in patients with moderate-to-severe atopic dermatitis: Randomized, phase II, long-term extension study.

BACKGROUND: Nemolizumab, an anti-IL-31 receptor A mAb, improved pruritus, dermatitis, and sleep in adults with moderate-to-severe atopic dermatitis that was inadequately controlled by topical treatments in a phase II, 12-week, randomized, double-blind, placebo-controlled study (part A; NCT01986933). OBJECTIVE: We sought to assess the long-term efficacy and safety of nemolizumab injected subcutaneously every 4 weeks (Q4W) or every 8 weeks (Q8W) in a 52-week, double-blind extension (part B). METHODS: During part B, patients continued the previous nemolizumab dose (0.1, 0.5, or 2.0 mg/kg Q4W or 2.0 mg/kg Q8W). Part B end points included percentage improvement from baseline in pruritus visual analog scale and dermatitis scores (including the Eczema Area and Severity Index). RESULTS: Overall, 216 of 264 patients completed part A, and 191 entered part B; 131 completed part B. In 153 patients randomized to nemolizumab in part A, improvement from baseline in pruritus visual analog scale score was maintained/increased from weeks 12 to 64, with greatest improvement in the 0.5-mg/kg Q4W group (percentage change from baseline at week 64: -73.0, -89.6, -74.7, and -79.1 in the 0.1-, 0.5-, and 2.0-mg/kg Q4W and 2.0-mg/kg Q8W groups, respectively). Improvement from baseline in dermatitis scores was also maintained/increased to week 64 (percentage change in Eczema Area and Severity Index score: -68.5, -75.8, -78.9, and -69.3 in the 0.1-, 0.5-, and 2.0-mg/kg Q4W and 2.0-mg/kg Q8W groups, respectively). Over 64 weeks, 83% to 89% had 1 or more adverse events, with no new safety concerns identified. CONCLUSION: Nemolizumab for up to 64 weeks was efficacious and overall well tolerated in patients with moderate-to-severe atopic dermatitis inadequately controlled by topical therapy.

Pharmacokinetics of a novel human intravenous immunoglobulin 10% in patients with primary immunodeficiency diseases: Analysis of a phase III, multicentre, prospective, open-label study.

Intravenous immunoglobulin (IVIG) therapy is commonly used to treat patients with primary antibody deficiency. This prospective, open-label, non-randomised, multicentre, phase III trial investigated the pharmacokinetics of a new 10% liquid IVIG product (panzyga®; Octapharma) in 51 patients aged 2-75 years with common variable immunodeficiency (n = 43) or X-linked agammaglobulinaemia (n = 8). Patients were treated with IVIG 10% every 3 (n = 21) or 4 weeks (n = 30) at a dose of 200-800 mg/kg for 12 months. Total immunoglobulin G (IgG) and subclass concentrations approximately doubled from pre- to 15 min post-infusion. The maximum concentration of total IgG (mean ±â€¯SD) was 21.82 ±â€¯5.83 g/L in patients treated 3-weekly and 17.42 ±â€¯3.34 g/L in patients treated 4-weekly. Median trough IgG concentrations were nearly constant over the course of the study, remaining between 11.0 and 12.2 g/L for patients on the 3-week schedule and between 8.10 and 8.65 g/L for patients on the 4-week schedule. The median terminal half-life of total IgG was 36.1 (range 18.5-65.9) days, with generally similar values for the IgG subclasses (26.7-38.0 days). Median half-lives for specific antibodies ranged between 21.3 and 51.2 days for anti-cytomegalovirus, anti-Haemophilus influenzae, anti-measles, anti-tetanus toxoid, anti-varicella zoster virus antibodies, and anti-Streptococcus pneumoniae subtype antibodies. Overall, IVIG 10% demonstrated pharmacokinetic properties similar to those of other commercial IVIG 10% preparations and 3- or 4-weekly administration achieved sufficient concentrations of IgG, IgG subclasses, and specific antibodies, exceeding the recommended level needed to effectively prevent serious bacterial infections.

Impaired fibrinolysis and lower levels of plasma α2-macroglobulin are associated with an increased risk of severe asthma exacerbations.

Recently we have reported that asthma is associated with enhanced plasma thrombin formation, impaired fibrinolysis and platelet activation. In the present study we investigated whether described prothrombotic blood alterations might predispose to thromboembolic events or asthma exacerbations. In 164 adult asthmatics we assessed clinical events during 3-year follow-up and analyzed their associations with measured at baseline prothrombotic blood parameters. Data were obtained from 157 (95.7%) of the asthma patients. We documented 198 severe asthma exacerbations (64/year), which occurred in 53 subjects (34%). These patients were older (p = 0.004), had worse asthma control (p = 0.02) and lower spirometry values (p = 0.01), at baseline. Interestingly, this subgroup had longer clot lysis time (CLT), as well as lower α2-macroglobulin (p = 0.038 and p = 0.04, respectively, after adjustment for potential confounders). Increased CLT and lower α2-macroglobulin were demonstrated as independent predictors of asthma exacerbation in multiple regression model. Moreover, we documented two episodes of deep vein thrombosis (1.3%), and eight acute coronary syndromes (5.1%). Patients who experienced thromboembolic events (n = 10, 6.4%, 2.1%/year) had lower α2-macroglobulin (p = 0.04), without differences in efficiency of fibrinolysis and thrombin generation. Impaired fibrinolysis and lower levels of α2-macroglobulin might predispose to a higher rate of asthma exacerbations, suggesting new links between disturbed hemostasis and asthma.

Efficacy and Safety of Human Intravenous Immunoglobulin 10% (Panzyga®) in Patients with Primary Immunodeficiency Diseases: a Two-Stage, Multicenter, Prospective, Open-Label Study.

PURPOSE: To assess the efficacy and safety of panzyga® (intravenous immunoglobulin 10%) in preventing serious bacterial infections (SBIs) in patients with primary immunodeficiency diseases (PIDs), a prospective, open-label, multicenter, phase 3 study and an open-label extension study were undertaken. METHODS: Initially, the study drug (infusion rate ≤0.08 mL/kg/min) was administered at intervals of 3 or 4 weeks for 12 months, followed by 3 months of panzyga® at infusion rates increasing from 0.08 to 0.14 mL/kg/min. The primary endpoint in the main study was the rate of SBIs per patient-year on treatment. Secondary outcomes included non-serious infections, work/school absence, episodes of fever, quality of life, and adverse events (AEs). RESULTS: The main study enrolled 51 patients (35% female, mean age 26.8 years), with 21 participating in the extension study. The rate of SBIs per patient-year was 0.08 in the total population; there were four SBIs in the 4-weekly treatment group (2/30 patients) and none in the 3-weekly group (n = 21). Compared with 4-weekly treatment, 3-weekly treatment was associated with a higher rate of upper respiratory tract infections (RTIs), ear infections, and work/school absences, but a lower rate of lower RTIs and fever. Treatment was generally well tolerated; no AE led to treatment withdrawal or death. CONCLUSIONS: Overall, the use of panzyga® in patients with antibody-deficient PID was associated with a low rate of AEs and was effective in preventing SBIs, exceeding US FDA and European Medicines Agency recommendations for efficacy.

Prothrombotic State in Asthma Is Related to Increased Levels of Inflammatory Cytokines, IL-6 and TNFα, in Peripheral Blood.

Recently, we have reported that asthma is associated with enhanced plasma thrombin formation and impaired fibrinolysis. The mechanisms underlying the prothrombotic state in this disease are unknown. Our aim was to investigate whether prothrombotic alterations in asthmatics are associated with inflammation. We studied 164 adult, white, stable asthmatics and 72 controls matched for age, sex, body mass index (BMI), and smoking. Plasma tumor necrosis factor α (TNFα), interleukin (IL)-6, and serum periostin were evaluated using ELISAs, and their associations with thrombin generation, fibrinolytic capacity, expressed as clot lysis time (CLT), and platelet markers were later analyzed. Asthma was characterized by 62% higher plasma IL-6 and 35% higher TNFα (both, p < 0.0001). Inflammatory cytokines were higher in sporadic and persistent asthmatics compared to controls, also after adjustment for potential confounders. IL-6 was inversely related to the forced expiratory volume in 1 s/vital capacity (FEV1/VC) spirometry index after correction for age, sex, and BMI. IL-6 and TNFα were associated with C-reactive protein in asthmatics (ß = 0.6 [95% CI, 0.54-0.67] and ß = 0.33 [95% CI, 0.25-0.41], respectively) and controls (ß = 0.43 [95% CI, 0.29-0.57] and ß = 0.33 [95% CI, 0.18-0.48], respectively). In asthma, IL-6 and TNFα positively correlated with the endogenous thrombin potential (ß = 0.35 [95% CI, 0.28-0.42] and ß = 0.15 [95% CI, 0.07-0.23], respectively) but not with CLT or platelet markers. However, TNFα predicted CLT in a multiple linear regression model. Periostin was not associated with any hemostatic parameters. Enhanced thrombin generation is driven in asthma by a systemic inflammatory state mediated by IL-6 and to a lesser extent TNFα, however, not periostin. TNFα might contribute to impaired fibrinolysis.

Anti-Interleukin-31 Receptor A Antibody for Atopic Dermatitis.

BACKGROUND: Interleukin-31 may play a role in the pathobiologic mechanism of atopic dermatitis and pruritus. We wanted to assess the efficacy and safety of nemolizumab (CIM331), a humanized antibody against interleukin-31 receptor A, in the treatment of atopic dermatitis. METHODS: In this phase 2, randomized, double-blind, placebo-controlled, 12-week trial, we assigned adults with moderate-to-severe atopic dermatitis that was inadequately controlled by topical treatments to receive subcutaneous nemolizumab (at a dose of 0.1 mg, 0.5 mg, or 2.0 mg per kilogram of body weight) or placebo every 4 weeks or an exploratory dose of 2.0 mg of nemolizumab per kilogram every 8 weeks. The primary end point was the percentage improvement from baseline in the score on the pruritus visual-analogue scale (on which a negative change indicates improvement) at week 12. Secondary end points included changes in the score on the Eczema Area and Severity Index (EASI, on which a negative change indicates improvement), and body-surface area of atopic dermatitis. RESULTS: Of 264 patients who underwent randomization, 216 (82%) completed the study. At week 12, among the patients who received nemolizumab every 4 weeks, changes on the pruritus visual-analogue scale were -43.7% in the 0.1-mg group, -59.8% in the 0.5-mg group, and -63.1% in the 2.0-mg group, versus -20.9% in the placebo group (P<0.01 for all comparisons). Changes on the EASI were -23.0%, -42.3%, and -40.9%, respectively, in the nemolizumab groups, versus -26.6% in the placebo group. Respective changes in body-surface area affected by atopic dermatitis were -7.5%, -20.0%, and -19.4% with nemolizumab, versus -15.7% with placebo. Among the patients receiving nemolizumab every 4 weeks, treatment discontinuations occurred in 9 of 53 patients (17%) in the 0.1-mg group, in 9 of 54 (17%) in the 0.5-mg group, and in 7 of 52 (13%) in the 2.0-mg group, versus in 9 of 53 (17%) in the placebo group. CONCLUSIONS: In this phase 2 trial, nemolizumab at all monthly doses significantly improved pruritus in patients with moderate-to-severe atopic dermatitis, which showed the efficacy of targeting interleukin-31 receptor A. The limited size and length of the trial preclude conclusions regarding adverse events. (Funded by Chugai Pharmaceutical; XCIMA ClinicalTrials.gov number, NCT01986933 .).

Evaluation of the quality of life in subjects with a history of severe anaphylactic reaction to the Hymenoptera venom.

INTRODUCTION: Sensitization to the Hymenoptera venom is one of the main causes of anaphylaxis in Poland. Venom immunotherapy is the only effective treatment in such cases. Comprehensive patient care includes also education. The aim of our study was to assess the state of knowledge and to evaluate the quality of life and the anxiety level in patients allergic to the Hymenoptera venom after anaphylactic reaction. MATERIAL AND METHODS: The survey was carried out in the period of the insects flight in 61 adult subjects (35 wasp and 26 bee allergic), using a validated Vespid Allergy Quality of Life Questionnaire (VQLQ), Hospital Anxiety and Depression Scale, and subjective assessment of anxiety level. The majority of respondents received venom immunotherapy. RESULTS: Sensitized to the wasp venom had significantly impaired quality of life (VQLQ score) as compared to the bee venom allergic (p = 0.014). The intensity of anxiety decreased with the duration of immunotherapy (p = 0.01). The majority of subjects knew how to recognize and treat anaphylaxis, but only 8% employed an identification card and about 50% implemented rules of the pre-exposition prophylaxis. CONCLUSIONS: History of a severe anaphylaxis to the Hymenoptera venom affected the quality of life. Venom immunotherapy reduced anxiety. We hope that presented surveys and their results might be useful in qualifying for immunotherapy in clinically uncertain cases.

Assessment of remodeling in chronic obstructive pulmonary disease using imaging methods.

INTRODUCTION: While spirometry plays a key role in diagnosing chronic obstructive pulmonary disease (COPD), imaging methods including endobronchial ultrasound (EBUS) and chest computed tomography (CT) appear to be useful for investigating structural changes in the lungs. OBJECTIVES: The aim of this study was to evaluate remodeling in COPD patients using EBUS and chest CT. PATIENTS AND METHODS: The study included 33 patients with COPD, 15 patients with severe asthma, and 15 control subjects. All subjects underwent pulmonary function tests and bronchoscopy with EBUS to measure the total thickness of the bronchial wall and its layers. Additionally, in COPD patients, a chest CT was performed to measure total bronchial wall thickness. RESULTS: The total bronchial wall thickness measured by EBUS in patients with COPD (1.192 ±0.079 mm) was significantly smaller than that in asthmatic patients (1.433 ±0.230 mm, P = 0.001) and significantly greater than in control subjects (1.099 ±0.095 mm, P = 0.04), and was positively correlated with residual volume (RV) / total lung capacity (r = 0.5, P = 0.02), RV (r = 0.6, P = 0.007), and RV (%) (r = 0.5, P = 0.05). The thickness of the bronchial wall layers in patients with COPD were as follows: L1 = 0.135 ±0.018 mm, L2 = 0.151 ±0.026 mm, and L3-5 = 0.906 ±0.065 mm. There was no correlation between the thickness of the bronchial wall layers and forced expiratory volume in 1 second. CONCLUSIONS: The results of this study show that EBUS is a useful method for evaluating bronchial wall layers not only in asthma but also in COPD, and suggest that the pattern of remodeling differs in each of these diseases.

[The significance of selected psychopathological and personality variables in the course of allergic and non-allergic asthma]. / Znaczenie wybranych zmiennych psychopatologicznych i osobowosciowych w przebiegu astmy oskrzelowej alergicznej i niealergicznej.

AIM: The aim of this study was to carry out a comparative analysis of selected psychopathological and personality variables in patients with allergic and non-allergic asthma, as well as an attempt to determine the significance and strength of these variables in the clinical picture of both forms of the disease. METHODS: In all patients structured anamnesis, basic spirometry, and dyspnea measure- ment were carried out. The level of anxiety was determined using Spielberger's questionnaire. The intensity of depression was evaluated with Beck's Inventory. Neuroticism and extroversion-introversion were assessed by Eysenck's Inventory. The I-E scale was used to determine the perception of the locus of control. RESULTS: The lack of significant differences in the area ofpsychopathological and personality variables was found between the two types of asthma. The gender differentiated patients with respect to psychopathology. The intensity of extroversion correlated with the duration of the disease. In the case of neuroticism, the clinical form of the disease was associated with blurring the differences between genders. The intensity of dyspnea and the spirometric results correlated with the psychological background of the disease. CONCLUSIONS: No significant differences in the area of psychopathology and personality dimensions between the groups of patients with allergic and non-allergic asthma were found although psychological variables are associated with the course of asthma in adults.

Increased expression of α2 (CD49b), α4 (CD49d) and ß1 (CD29) integrin subunits on peripheral blood T lymphocytes in clinically stable mild-to-moderate persistent asthma.

INTRODUCTION: Adhesive molecules, particularly selectins and integrins, are critical for the inflammatory cell trafficking from blood to the lungs. Among integrins, the most important for cell infiltration are those containing α4 and ß2 subunits. OBJECTIVES: The aim of this study was to evaluate the expression of α1 and α2 integrin subunits on peripheral blood T cells in asthmatic subjects, because previously we showed evidence that α1ß1 and α2ß1 integrins may be found on peripheral blood eosinophils in these subjects. In this study, we also analyzed the expression of α4 and ß1 subunits as a positive reference. PATIENTS AND METHODS: Expression of α1, α2, α4, and ß1 subunits was analyzed by flow cytometry on CD4+ and CD8+ T lymphocytes obtained from the peripheral blood of 54 clinically stable, asymptomatic, mild-to-moderate persistent asthmatics and 40 healthy controls. RESULTS: The α1 subunit was not present on peripheral blood T cells in the majority of subjects in both study groups. Expression of α2 was detectable on CD8+ cells in both groups and was increased on CD4+ in asthmatics. Both types of T cells showed higher expression of α4 and ß1 in patients with asthma. Expression of α4 was higher on CD8+ T cells both in asthmatics and controls. CONCLUSIONS: Expression of α4 and ß1 integrin subunits is increased on peripheral blood T cells in patients with asthma, which confirms the preactivation of blood lymphocytes even in stable and asymptomatic disease. The biological role of α2 subunit on T cells remains to be elucidated.

[Measurement of bronchoconstrictive eicosanoids in chronic obstructive pulmonary disease]. / Pomiar bronchospastycznych eikozanoidów w przewleklejobturacyjnej chorobie pluc.

INTRODUCTION: The aim of the study was the evaluation of the concentration of 9α11ß prostaglandin F(2) - a stable metabolite of prostaglandin D(2) (PGD(2)) and leukotriene E(4) (LTE(4)) in stable and exacerbated COPD patients. MATERIAL AND METHODS: 29 COPD patients aged 73 ± 8.34, mean FEV1 = 48.64 ± 15.75% of predictive value and 29 healthy controls aged 57.48 ± 10.86, mean FEV1 = 97.17 ± 13.81% of predictive value participated in this study. Samples of urine and blood were taken from COPD patients during exacerbation and in stable state of the disease; LTE(4) was determined in urine using commercial enzyme immunoassay (EIA) and 9α11ß prostaglandin F(2) (9α11ßPGF(2)) - stable metabolite of PGD(2) was evaluated in blood and urine using GC/MS. RESULTS: LTE(4) concentration in urine (677.15 vs. 436.4 pg/mg of creatinine; p = 0.035) and 9α11ßPGF(2) in blood serum (5.35 vs. 3.07 pg/ml; p = 0.007) were significantly higher in exacerbated COPD patients than in control group. There was no difference in LTE(4) level in urine and 9α11ßPGF2 in blood serum between exacerbated and stable COPD. The urinary 9α11ßPGF(2) concentration did not differ between all studied groups. We found a positive correlation between smoking history and the urine LTE(4) level (r = 0.395; p = 0.002) as well as blood 9α11ßPGF(2) concentration (r = 0.603; p = 0.001) in COPD patients. CONCLUSIONS: 9α11ßPGF(2) and LTE(4) level in urine did not differ between the stable COPD group and the control group. We also did not find any difference between LTE4 level in urine and 9α11ßPGF(2) in blood and urine between exacerbated and stable COPD. Finally, LTE(4) concentration in urine and 9α11ßPGF(2) in blood occurred to be significantly higher in exacerbated COPD patients than in control group.

Efficacy and safety of fluticasone and formoterol in a single pressurized metered dose inhaler.

BACKGROUND: Fluticasone and formoterol are well established medications for the treatment of asthma. This study (Clinicaltrials.gov identifier: NCT00734318) compares the efficacy and safety of a combination of these drugs in a single inhaler (fluticasone/formoterol) versus the individual components (fluticasone + formoterol). METHODS: Patients aged ≥ 18 years (n=620) with a history of severe, persistent reversible asthma for ≥ 6 months prior to screening were included in this randomized, double-blind study, which consisted of a screening phase of up to 5 days, a 2-week run-in phase and an 8-week treatment period. RESULTS: Fluticasone/formoterol (500/20 µg, b.i.d.) was at least as effective as fluticasone + formoterol (500 µg + 24 µg, b.i.d.) with respect to the primary outcome measure: there were similar increases in mean pre-morning dose forced expiratory volume in the first second (FEV(1)) in these two groups. Fluticasone/formoterol (500/20 µg, b.i.d.) also demonstrated similar efficacy to fluticasone + formoterol in terms of change in mean FEV(1) from baseline pre-morning dose to 2 h post-morning dose at week 8, as well as for several secondary parameters. Fluticasone/formoterol (500/20 µg, b.i.d.) demonstrated superiority to fluticasone monotherapy (500 µg, b.i.d.) and fluticasone/formoterol (100/10 µg, b.i.d.) for several secondary efficacy parameters. Fluticasone/formoterol had a similar safety and tolerability profile to fluticasone + formoterol. CONCLUSION: This study demonstrated that the fluticasone/formoterol combination is at least as effective as its components administered concurrently from separate inhalers. Fluticasone/formoterol (500/20 µg, b.i.d.) showed superior efficacy to its inhaled corticosteroid component alone and the efficacy of fluticasone/formoterol was dose-dependent for several clinically important parameters.

The use of endobronchial ultrasonography in assessment of bronchial wall remodeling in patients with asthma.

BACKGROUND: Endobronchial ultrasound (EBUS) is a new technique that enables the assessment of bronchial wall layers. The aim of the study was to verify the utility of EBUS for the assessment of bronchial wall remodeling in patients with asthma. METHODS: In 35 patients with asthma and 23 control subjects, high-resolution CT (HRCT) scanning and EBUS were used to measure bronchial wall thickness in the 10th segment of the right lung. With a radial 20-MHz probe, EBUS identified the 5-laminar structure of the bronchial wall. Layer 1 (L(1)) and layer 2 (L(2)) were analyzed separately, and layers 3 through 5 (L(3-5)), which corresponded to cartilage, were analyzed jointly. Digitalized EBUS images were used for the quantitative assessment of bronchial wall thickness and the wall area (WA) of the layers. Finally, bronchial biopsy specimens were taken for measuring the thickness of the reticular basement membrane (RBM). The thickness and WA of the bronchial wall layers, which were assessed using EBUS, were correlated with FEV(1) and RBM. RESULTS: There was no significant difference in the measurements of total bronchial wall thickness using EBUS and HRCT scanning. The thickness and WA of the bronchial wall and its layers were significantly greater in patients with asthma than in the control subjects. A negative correlation among the thicknesses of L(1), L(2), and L(3-5) and FEV(1), and a positive correlation with RBM were observed only in the patients with asthma. CONCLUSIONS: EBUS allows precise measurement of the thickness and WA of bronchial wall layers. The correlation of these parameters with asthma severity suggests implementation of EBUS in the assessment of bronchial wall remodeling in patients with asthma.

High-resolution computed tomography evaluation of peripheral airways in asthma patients: comparison of focal and diffuse air trapping.

BACKGROUND: Air trapping evaluated in high-resolution computed tomography (HRCT) reflects changes in small bronchi. We simultaneously evaluated focal and diffuse air trapping in asthmatic patients. OBJECTIVES: (1) To evaluate air trapping and bronchial wall thickness in asthmatics. (2) To estimate the relationship between air trapping and bronchial wall thickness, pulmonary function tests (PFTs), age, gender and asthma severity. (3) To compare air trapping between subgroups of asthmatic patients with normal FEV(1) % pred. and FEV(1)/FVC % and controls. (4) To compare air trapping and bronchial wall thickness between aspirin-induced asthmatics (AIA) and aspirin-tolerant asthmatics (ATA). METHODS: Both groups (asthmatics and controls) included 30 patients. All patients underwent HRCT and PFTs. RESULTS: Focal (p < 0.0001) and diffuse (p = 0.0004) air trappings and bronchial wall thickness (T: p < 0.0001; T/D: p < 0.0001; WA%: p < 0.0001) were significantly greater in asthmatics. Focal and diffuse air trappings were inversely correlated (p = 0.021). Diffuse air trapping correlated with bronchial wall thickness: T/D (p = 0.047), T (p = 0.037), and WA% (p = 0.048). There was a significant difference in the extent of focal air trapping between a subgroup of asthmatics with normal FEV(1) % pred. and FEV(1)/FVC % and controls (p < 0.0001). There were no significant differences in focal (p = 0.095) and diffuse air trapping (p = 0.186) and bronchial wall thickness (T: p = 0.086; T/D: p = 0.428; WA%: p = 0.428) between AIA and ATA patients. CONCLUSIONS: Both focal and diffuse air trappings provide valuable diagnostic information and therefore deserve to be estimated. The lack of significant differences in air trapping and bronchial wall thickness between AIA and ATA patients needs further investigation.