Periostin, also termed osteoblast-specific factor 2, is a matricellular protein with known functions in osteology, tissue repair, oncology, cardiovascular and respiratory systems, and in various ...inflammatory settings. However, most of the research to date has been conducted in divergent and circumscribed areas meaning that the overall understanding of this intriguing molecule remains fragmented. Here, we integrate the available evidence on periostin expression, its normal role in development, and whether it plays a similar function during pathologic repair, regeneration, and disease in order to bring together the different research fields in which periostin investigations are ongoing. In spite of the seemingly disparate roles of periostin in health and disease, tissue remodeling as a response to insult/injury is emerging as a common functional denominator of this matricellular molecule. Periostin is transiently upregulated during cell fate changes, either physiologic or pathologic. Combining observations from various conditions, a common pattern of events can be suggested, including periostin localization during development, insult and injury, epithelial–mesenchymal transition, extracellular matrix restructuring, and remodeling. We propose mesenchymal remodeling as an overarching role for the matricellular protein periostin, across physiology and disease. Periostin may be seen as an important structural mediator, balancing appropriate versus inappropriate tissue adaption in response to insult/injury.
Background
Current biologic therapies target allergic, eosinophilic or type 2 inflammation phenotypic asthma. However, frequency and degree of overlap among these subtypes is unclear.
Objective
To ...characterize overlap among allergic, eosinophilic and type 2 asthma phenotypes.
Methods
Post hoc analyses of baseline data were performed in two adult populations: (a) not selected for any asthma subtype (N = 935) and (b) selected for allergic asthma (N = 1049). Degree of overlap was examined using commonly accepted phenotypic definitions to guide treatment for allergic asthma (skin prick–positive and/or positive serum–specific immunoglobulin E > 0.35 kU/L) and eosinophilic asthma (blood eosinophil high count ≥ 300 cells/µL; low cut‐off ≥ 150 cells/µL). Consistent with previous studies, fractional exhaled nitric oxide high level of ≥ 35 ppb and low cut‐off of ≥ 25 ppb were selected as local markers of type 2 inflammation and to prevent overlap with the systemic eosinophilic asthma definition.
Results
In the non‐subtype–selected population, 78.0% had allergic asthma; of these, 39.5% had eosinophilic asthma and 29.5% had type 2 asthma. Within patients with eosinophilic asthma (40.6% of total), 75.8% had allergic asthma and 41.3% had type 2 asthma. Within patients with type 2 asthma (28.3% of total), 81.1% had allergic asthma and 59.2% had eosinophilic asthma. In the allergic asthma–selected population, 38.3% had eosinophilic asthma and 29.2% had type 2 asthma. Within patients with eosinophilic asthma, 46.3% had type 2 asthma. Within patients with type 2 asthma, 60.8% had eosinophilic asthma. Overlaps among subtypes increased at low cut‐off values.
Conclusions and clinical relevance
In this post hoc analysis in adults with moderate‐to‐severe asthma, allergic asthma was the most prevalent phenotype, followed by eosinophilic and type 2 asthma. Despite observed overlaps, a considerable proportion of patients had only a predominantly allergic subtype. Understanding the degree of overlap across phenotypes will help patient management and guide treatment options.
In a subset of patients with asthma, standard-of-care treatment does not achieve disease control, highlighting the need for novel therapeutic approaches. Lebrikizumab is a humanised, monoclonal ...antibody that binds to and blocks interleukin-13 activity.
LUTE and VERSE were replicate, randomised, double-blind, placebo-controlled studies, evaluating multiple doses of lebrikizumab in patients with uncontrolled asthma despite the use of medium-to-high-dose inhaled corticosteroid and a second controller. Patients received lebrikizumab 37.5, 125, 250 mg or placebo subcutaneously every four weeks. The primary endpoint was the rate of asthma exacerbations during the placebo-controlled period. Analyses were performed on prespecified subgroups based on baseline serum periostin levels. Following the discovery of a host-cell impurity in the study drug material, protocols were amended to convert from phase III to phase IIb. Subsequently, dosing of study medication was discontinued early as a precautionary measure. The data collected for analysis were from a placebo-controlled period of variable duration and pooled across both studies.
The median duration of treatment was approximately 24 weeks. Treatment with lebrikizumab reduced the rate of asthma exacerbations, which was more pronounced in the periostin-high patients (all doses: 60% reduction) than in the periostin-low patients (all doses: 5% reduction); no dose-response was evident. Lung function also improved following lebrikizumab treatment, with greatest increase in FEV1 in periostin-high patients (all doses: 9.1% placebo-adjusted improvement) compared with periostin-low patients (all doses: 2.6% placebo-adjusted improvement). Lebrikizumab was well tolerated and no clinically important safety signals were observed.
These data are consistent with, and extend, previously published results demonstrating the efficacy of lebrikizumab in improving rate of asthma exacerbations and lung function in patients with moderate-to-severe asthma who remain uncontrolled despite current standard-of-care treatment.
The LUTE study was registered under NCT01545440 and the VERSE study under NCT01545453 at http://www.clinicaltrials.gov.
Roles of Periostin in Respiratory Disorders Izuhara, Kenji; Conway, Simon J; Moore, Bethany B ...
American journal of respiratory and critical care medicine,
05/2016, Letnik:
193, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Periostin is a matricellular protein that has been implicated in many disease states. It interacts with multiple signaling cascades to modulate the expression of downstream genes that regulate ...cellular interactions within the extracellular matrix. This review focuses on the role of periostin in respiratory diseases, including asthma and idiopathic pulmonary fibrosis, and its potential to help guide treatment or assess prognosis. Epithelial injury is a common feature of many respiratory diseases, resulting in the secretion, among others, of periostin, which is subsequently involved in airway remodeling and other aspects of pulmonary pathophysiology. In asthma, periostin is recognized as a biomarker of type 2 inflammation; POSTN gene expression is up-regulated in bronchial epithelial cells by IL-13 and IL-4. Serum periostin has been evaluated for the identification of patients with increased clinical benefit from treatment with anti-IL-13 (lebrikizumab, tralokinumab) and anti-IgE (omalizumab) therapy and may be prognostic for increased risk of asthma exacerbations and progressive lung function decline. Furthermore, in asthma, periostin may regulate subepithelial fibrosis and mucus production and may serve as a systemic biomarker of eosinophilic airway inflammation. Periostin is also highly expressed in the lungs of patients with idiopathic pulmonary fibrosis, and its serum levels may predict clinical progression. Overall, periostin contributes to multiple pathogenic processes across respiratory diseases, and peripheral blood levels of periostin may have utility as a biomarker of treatment response and disease progression.
Rheumatoid arthritis (RA) is a complex and clinically heterogeneous autoimmune disease. Currently, the relationship between pathogenic molecular drivers of disease in RA and therapeutic response is ...poorly understood.
We analyzed synovial tissue samples from two RA cohorts of 49 and 20 patients using a combination of global gene expression, histologic and cellular analyses, and analysis of gene expression data from two further publicly available RA cohorts. To identify candidate serum biomarkers that correspond to differential synovial biology and clinical response to targeted therapies, we performed pre-treatment biomarker analysis compared with therapeutic outcome at week 24 in serum samples from 198 patients from the ADACTA (ADalimumab ACTemrA) phase 4 trial of tocilizumab (anti-IL-6R) monotherapy versus adalimumab (anti-TNFα) monotherapy.
We documented evidence for four major phenotypes of RA synovium - lymphoid, myeloid, low inflammatory, and fibroid - each with distinct underlying gene expression signatures. We observed that baseline synovial myeloid, but not lymphoid, gene signature expression was higher in patients with good compared with poor European league against rheumatism (EULAR) clinical response to anti-TNFα therapy at week 16 (P =0.011). We observed that high baseline serum soluble intercellular adhesion molecule 1 (sICAM1), associated with the myeloid phenotype, and high serum C-X-C motif chemokine 13 (CXCL13), associated with the lymphoid phenotype, had differential relationships with clinical response to anti-TNFα compared with anti-IL6R treatment. sICAM1-high/CXCL13-low patients showed the highest week 24 American College of Rheumatology (ACR) 50 response rate to anti-TNFα treatment as compared with sICAM1-low/CXCL13-high patients (42% versus 13%, respectively, P =0.05) while anti-IL-6R patients showed the opposite relationship with these biomarker subgroups (ACR50 20% versus 69%, P =0.004).
These data demonstrate that underlying molecular and cellular heterogeneity in RA impacts clinical outcome to therapies targeting different biological pathways, with patients with the myeloid phenotype exhibiting the most robust response to anti-TNFα. These data suggest a path to identify and validate serum biomarkers that predict response to targeted therapies in rheumatoid arthritis and possibly other autoimmune diseases.
ClinicalTrials.gov NCT01119859
Background Biomarkers, preferably noninvasive, that predict asthma inception in children are lacking. Objective Little is known about biomarkers of type 2 inflammation in early life in relation to ...asthma inception. We evaluated aeroallergen sensitization, peripheral blood eosinophils, and serum periostin as potential biomarkers of asthma in children. Methods Children enrolled in the Childhood Origins of ASThma study were followed prospectively from birth. Blood samples were collected at ages 2, 4, 6, and 11 years, and serum-specific IgE levels, blood eosionophil counts, and periostin levels were measured in 244 children. Relationships among these biomarkers, age, and asthma were assessed. Results Serum periostin levels were approximately 2- to 3-fold higher in children than previously observed adult levels. Levels were highest at 2 years (145 ng/mL), and did not change significantly between 4 and 11 years (128 and 130 ng/mL). Age 2 year periostin level of 150 ng/mL or more predicted asthma at age 6 years (odds ratio OR, 2.3; 95% CI, 1.3-4.4). Eosinophil count of 300 cells/μL or more and aeroallergen sensitization at age 2 years were each associated with increased risk of asthma at age 6 years (OR, 3.1; 95% CI, 1.7-6.0 and OR, 3.3; 95% CI, 1.7-6.3). Children with any 2 of the biomarkers had a significantly increased risk of developing asthma by school age (≥2 biomarkers vs none: OR, 6.6; 95% CI, 2.7-16.0). Conclusions Serum periostin levels are significantly higher in children than in adults, likely due to bone turnover, which impairs clinical utility in children. Early life aeroallergen sensitization and elevated blood eosinophils are robust predictors of asthma development. Children with evidence of activation of multiple pathways of type 2 inflammation in early life are at greatest risk for asthma development.
...the aim of this study was to investigate whether serum (s) periostin is elevated in patients with CRSwNP compared with patients with CRSsNP and controls, and to evaluate whether s-periostin and ...other inflammatory markers could be used as serum biomarkers to identify patients with CRSwNP with IL-5 and/or SE-IgE tissue (t) expression, representing moderate and severe endotypes of CRSwNP according to the formerly mentioned cluster analysis.2 In total 377 patients participating in the Global Allergy and Asthma European Network study were included, divided into CRSwNP (n = 144), CRSsNP (n = 123), and controls (n = 110) on the basis of history and nasal endoscopy. ...our results show that s-periostin is elevated in patients with CRSwNP. Measurement of inflammatory markers Nasal tissue of 0.1 g was diluted in 1 mL of 0.9% NaCl solution containing a protease inhibitor cocktail (Complete; Roche Diagnostics, Mannheim, Germany), homogenized at 1000 rpm for 5 minutes, and centrifuged at 1500g for 10 minutes at 4°C as described before.E2 Serum and tissue homogenate concentrations of total IgE, specific IgE to a mixture of S aureus enterotoxins (staphylococcal enterotoxins A and C and toxic shock syndrome toxin 1), and eosinophil cationic protein were assayed by using the UniCAP system (Phadia, Uppsala, Sweden). Parameter CRSwNP CRSsNP Controls P value CRSwNP vs CRSsNP (P value) CRSwNP vs controls (P value) CRSsNP vs controls (P value) Serum concentration, median (IQR) Periostin (ng/mL) 68.9 (57.1-86.6) 53.5 (46.4-64.3) 56.0 (48.3-67.8) <.0001∗ <.0001† <.0001† >.05† IgE (kU/L) 84.5 (36.2-231.4) 44.4 (16.1-113.5) 50.1 (13.4-131.5) <.001∗ <.001† <.01† >.05† SE-IgE (kUA/L) 0.13 (0-0.43) 0.07 (0-0.23) 0.08 (0-0.23) <.0001∗ <.001† <.0001† >.05† ECP (μg/L) 15.3 (7.7-28.9) 13.1 (6.8-21.6) 11.2 (5.5-18.9) <.01∗ <.01† <.01† >.05† sIL-5Rα (pg/mL) 318.5 (205.9-527.6) 239.4 (171.3-363) 219 (142.8-300.4) <.0001∗ <.001† <.0001† >.05† Proportion of patients above cutoff (numbers) in serum, % (n/N) Periostin > 48.5 ng/mL 93 (129/138) 72.7 (80/110) 75 (78/104) <.0001‡ <.0001§ <.0001§ >.05§ IgE >96 kU/L 44.4 (64/144) 28.4 (35/123) 30 (33/110) <.05‡ <.01§ <.05§ >.05§ SE-IgE >0.28 kUA/L 33.3 (48/144) 26 (32/123) 22.7 (25/110) >.05‡ >.05§ >.05§ >.05§ Tissue concentration, median (IQR) IgE U/g tissue 203.2 (72.1-529.7) 25.2 (7.3-76.6) 8.9 (1.9-22.3) <.0001∗ <.0001† <.0001† <.01† IL-5 pg/g tissue 132.3 (23.9-519.5) 0 (0-17.5) 0 (0-0) <.0001∗ <.0001† <.0001† <.0001† ECP μg/g tissue 4.626 (2.2-9.4) 0.83 (0.20-2.3) 0.11 (0.07-0.35) <.001∗ <.0001† <.0001† <.0001† Proportion of patients above cutoff (numbers) in tissue, % (n/N) IgE >0.35 U/g tissue 97.3 (110/113) 87.2 (82/94) 71.9 (64/89) <.0001‡ <.01§ <.0001§ <.05§ SE-IgE >0.35 UA/g tissue 20.3 (23/113) 3.2 (3/94) 0 (0/92) <.0001‡ <.001§ <.0001§ >.05§ IL-5 >6.6 pg/g tissue 83.9 (94/112) 32.3 (30/93)) 2.4 (2/84) <.0001‡ <.0001§ <.0001§ <.0001§ Table E1 Baseline characteristics of the cohort Characteristic CRSwNP CRSsNP Control Total N 144 123 110 377 Sex: male/female/missing 95/47/2 64/57/2 60/47/3 Age (y), mean (range) 45 (25-72) 40 (17-70) 32 (17-69) Body mass index, mean (range) 25.8 (18.1-34.8) 25.5 (17.1-39.6) 24.3 (17.7-33.4) Smoking pack-years, mean (range) 18.2 (1-40) 17.5 (2-41) 13.5 (1-50) Smoking ever, n (%) 83 (58) 80 (65) 52 (47) 215 (57) Smoking current, n (%) 23 (16) 46 (37) 26 (24) 95 (25) Asthma, n (%) 60 (42) 17 (14) 15 (10) 92 (24) Allergy, n (%) 63 (44) 61 (50) 39 (35) 163 (43) Allergic rhinitis, n (%) 42 (29) 39 (32) 26 (24) 107 (28) Aspirin intolerance, n (%) 14 (10) 2 (2) 1 (1) 15 (6) Table E2 Sensitivity and specificity of clinical signs for predicting the presence of IL-5 or SE-IgE in patients with CRSwNP∗ Parameter Sensitivity Specificity P value Tissue IL-5 positive Polyp score >3/6 60.7 84.6 <.005 Asthma 38 62.5 >.05 Tissue SE-IgE positive Polyp score >3/6 61.9 39.4 >.05 Asthma 54.6 64.3 >.05 1 C.A. Akdis, C. Bachert, C. Cingi, M.S. Dykewicz, P.W. Hellings, R.M. Naclerio, Endotypes and phenotypes of chronic rhinosinusitis: a PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology, J Allergy Clin Immunol, Vol. 131, 2013, 1479-1490 2 P. Tomassen, G. Vandeplas, T. Van Zele, L.O. Cardell, J. Arebro, H. Olze, Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers, J Allergy Clin Immunol, Vol. 137, 2016, 1449-1456.e4 3 G. Jia, R.W. Erickson, D.F. Choy, S. Mosesova, L.C. Wu, O.D. Solberg, Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients, J Allergy Clin Immunol, Vol. 130, 2012, 647-654.e10 4 N.A. Hanania, M. Noonan, J. Corren, P. Korenblat, Y. Zheng, S.K. Fischer, Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies, Thorax, Vol. 70, 2015, 748-756 5 N.A. Hanania, P. Korenblat, K.R. Chapman, E.D. Bateman, P. Kopecky, P. Paggiaro, Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II): replicate, phase 3, randomised, double-blind, placebo-controlled trials, Lancet Respir Med, Vol. 4, 2016, 781-796 6 M. Wang, X. Wang, N. Zhang, H. Wang, Y. Li, E. Fan, Association of periostin expression with eosinophilic inflammation in nasal polyps, J Allergy Clin Immunol, Vol. 136, 2015, 1700-1703, e1-9 7 J. Milonski, H. Zielinska-Blizniewska, K. Przybylowska, P. Pietkiewicz, B. Korzycka-Zaborowska, I. Majsterek, Significance of CYCLOOXYGENASE-2 (COX-2), PERIOSTIN (POSTN) and INTERLEUKIN-4(IL-4) gene expression in the pathogenesis of chronic rhinosinusitis with nasal polyps, Eur Arch Otorhinolaryngol, Vol. 272, 2015, 3715-3720
In phase 2 trials, lebrikizumab, an anti-interleukin-13 monoclonal antibody, reduced exacerbation rates and improved FEV
in patients with uncontrolled asthma, particularly in those with high ...concentrations of type 2 biomarkers (eg, periostin or blood eosinophils). We undertook replicate phase 3 studies to assess the efficacy and safety of lebrikizumab in patients with uncontrolled asthma despite inhaled corticosteroids and at least one second controller medication.
Adult patients with uncontrolled asthma, pre-bronchodilator FEV
40-80% predicted, and stable background therapy were randomly assigned (1:1:1) with an interactive voice-web-based response system to receive lebrikizumab 37·5 mg or 125 mg, or placebo subcutaneously, once every 4 weeks. Randomisation was stratified by screening serum periostin concentration, history of asthma exacerbations within the last 12 months, baseline asthma medications, and country. The primary efficacy endpoint was the rate of asthma exacerbations over 52 weeks in biomarker-high patients (periostin ≥50 ng/mL or blood eosinophils ≥300 cells per μL), analysed with a Poisson regression model corrected for overdispersion with Pearson χ
that included terms for treatment group, number of asthma exacerbations within the 12 months before study entry, baseline asthma medications, geographic region, screening periostin concentration, and blood eosinophil counts as covariates. Both trials are registered at ClinicalTrials.gov, LAVOLTA I, number NCT01867125, and LAVOLTA II, number NCT01868061.
1081 patients were treated in LAVOLTA I and 1067 patients in LAVOLTA II. Over 52 weeks, lebrikizumab reduced exacerbation rates in biomarker-high patients in the 37·5 mg dose group (rate ratio RR 0·49 95% CI 0·34-0·69, p<0·0001) and in the 125 mg dose group (RR 0·70 0·51-0·95, p=0·0232) versus placebo in LAVOLTA I. Exacerbation rates were also reduced in biomarker-high patients in both dose groups versus placebo in LAVOLTA II (37·5 mg: RR 0·74 95% CI 0·54-1·01, p=0·0609; 125 mg: RR 0·74 0·54-1·02, p=0·0626). Pooling both studies, the proportion of patients who experienced treatment-emergent adverse events (79% 1125 of 1432 patients for both lebrikizumab doses vs 80% 576 of 716 patients for placebo), serious adverse events (8% 115 patients for both lebrikizumab doses vs 9% 65 patients for placebo), and adverse events leading to study drug discontinuation (3% 49 patients for both lebrikizumab doses vs 4% 31 patients for placebo) were similar between lebrikizumab and placebo. The following serious adverse events were reported in the placebo-controlled period: one event of aplastic anaemia and five serious adverse events related to raised concentrations of eosinophils in patients treated with lebrikizumab and one event of eosinophilic pneumonia in the placebo group.
Lebrikizumab did not consistently show significant reduction in asthma exacerbations in biomarker-high patients. However, it blocked interleukin-13 as evidenced by the effect on interleukin-13-related pharmacodynamic biomarkers, and clinically relevant changes could not be ruled out.
F Hoffmann-La Roche.
Blood eosinophil counts are used to inform diagnosis/management of eosinophilic asthma.
Examine blood eosinophil variability and identify factors affecting eosinophil levels to inform clinical ...interpretation.
analysis to understand eosinophil variability using data from four randomized controlled asthma trials. We examined
) influence of intrinsic/extrinsic factors (comorbidities, medication, and patient history) using baseline data (
= 2,612);
) monthly variation using placebo-treated patient data (
= 713);
) stability of eosinophil classification (<150, 150-299, and ⩾300 cells/μl) in placebo-treated patients with monthly measurements over a 1-year period (
= 751); and
) impact of technical factors (laboratory-to-laboratory differences and time from collection to analysis).
Of intrinsic/extrinsic factors examined, nasal polyps increased eosinophil levels by 38%, whereas current smoking decreased levels by 23%. Substantial seasonal differences in eosinophil counts were observed, with differences of ∼20% between July and January. Eosinophil levels between 150 and 299 cells/μl were least stable, with 44% of patients remaining in the same classification for seven of 10 measurements versus 59% and 66% of patients in the <150 and ⩾300 cells/μl subgroups, respectively. Measurements at different laboratories showed high association (Spearman's correlation coefficient,
= 0.89); however, eosinophil counts were reduced, with longer time from collection to analysis, and variability increased with increasing eosinophil counts.
Several intrinsic, extrinsic, and technical factors may influence, and should be considered in, clinical interpretation of eosinophil counts. Additionally, a single measurement may not be sufficient when using eosinophil counts for diagnosis/management of eosinophilic asthma.
Background
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous disease with variable underlying pathophysiologies. Numerous patient factors have been linked to differences in disease ...severity, control, and response to treatment, including asthma status, aspirin sensitivity, previous sinonasal surgery, and blood eosinophil levels.
Objective
The present study examines the efficacy of the anti-immunoglobulin E therapy, omalizumab, versus placebo in patients with CRSwNP from the replicate POLYP 1 (NCT03280550) and POLYP 2 (NCT03280537) trials, grouped by inherent patient characteristics to determine the response to therapy.
Methods
Patients in prespecified subgroups from POLYP 1 and POLYP 2 (studies pooled for analysis) were examined. Subgroups included blood eosinophil count at baseline (>300 or ≤300 cells/μL), previous sinonasal surgery (yes or no), asthma status (yes or no), and aspirin sensitivity status (yes or no). Subgroups were examined for subgroup-specific adjusted mean difference (95% confidence interval CI) (omalizumab–placebo) in change from baseline at week 24 in Nasal Congestion Score (NCS), Nasal Polyp Score (NPS), Sino-Nasal Outcome Test-22 (SNOT-22), Total Nasal Symptom Score (TNSS), and University of Pennsylvania Smell Identification Test (UPSIT).
Results
Adjusted mean difference (95% CI) (omalizumab–placebo) in NCS, NPS, SNOT-22, TNSS, and UPSIT change from baseline at week 24 consistently favored omalizumab treatment over placebo in patients with blood eosinophil count >300 and ≤300 cells/μL, with or without previous sinonasal surgery, asthma, and aspirin sensitivity.
Conclusion
Together, these data suggest broad efficacy of omalizumab across clinical and patient-reported outcomes in patients with CRSwNP, independent of the underlying patient factors examined, including those with high eosinophil levels and those who have undergone previous surgery, which are associated with high recurrence.
Clinical Trial Registration
ClinicalTrials.gov identifiers: POLYP 1: ClinicalTrials.gov identifier NCT03280550 (https://clinicaltrials.gov/ct2/show/NCT03280550); POLYP 2: ClinicalTrials.gov identifier NCT03280537 (https://clinicaltrials.gov/ct2/show/NCT03280537).
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