Grazyna Pulka

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.)

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.

Increased expression of collagen receptors: α1β1 and α2β1 integrins on blood eosinophils in bronchial asthma

Background Eosinophils are one of the major effector cells in bronchial asthma. Their infiltration of airways correlates with the asthma severity. Recruitment and activation of eosinophils are partially mediated by integrins α4β1 and α4β7. Collagens type I and IV constitute important components of extracellular matrix and vascular basement membrane, respectively. Therefore, collagen‐binding integrins (α1β1 and α2β1) may also play a role in eosinophil lung infiltration.

Asthma is associated with enhanced thrombin formation and impaired fibrinolysis

There is evidence that altered blood coagulation and fibrinolysis are involved in the pathogenesis of asthma. Increased thromboembolic risk has been reported in asthmatics.

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 FEV1 % pred. and FEV1/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 FEV1 % pred. and FEV1/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.

Impaired fibrinolysis and lower levels of plasma α 2 -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.