Steroid-naive Patients Research Articles

Inhaler Steroid Use Changes Oral and Airway Bacterial and Fungal Microbiome Profile in Asthma Patients

Introduction: The full spectrum of bacterial and fungal species in adult asthma and the effect of inhaled corticosteroid use is not well described. The aim was to collect mouthwash and induced sputum samples from newly diagnosed asthma patients in the pretreatment period and in chronic asthma patients while undergoing regular maintenance inhaled corticosteroid therapy, in order to demonstrate the bacterial and fungal microbiome profile. Methods: The study included 28 asthmatic patients on inhaler steroid therapy, 25 steroid-naive asthmatics, and 24 healthy controls. Genomic DNA was isolated from induced sputum and mouthwash samples. Analyses were performed using bacterial primers selected from the 16S rRNA region for the bacterial genome and “panfungal” primers selected from the 5.8S rRNA region for the fungal genome. Results: Dominant genera in mouthwash samples of steroid-naive asthmatics were Neisseria, Haemophilus, and Rothia. The oral microbiota of asthmatic patients on inhaler steroid treatment included Neisseria, Rothia, and Veillonella species. Abundant genera in induced sputum samples of steroid-naive asthma patients were Actinomyces, Granulicatella, Fusobacterium, Peptostreptococcus, and Atopobium. Sputum microbiota of asthma patients taking inhaler steroids were dominated by Prevotella and Porphyromonas. Mucor plumbeus and Malassezia restricta species were abundant in the airways of steroid-naive asthma patients. Choanephora infundibulifera and Malassezia restricta became dominant in asthma patients taking inhaled steroids. Conclusion: The oral and airway microbiota consist of different bacterial and fungal communities in healthy and asthmatic patients. Inhaler steroid use may influence the composition of the oral and airway microbiota.

Mucosal α4β7+ Lymphocytes and MAdCAM+ Venules Predict Response to Vedolizumab in Ulcerative Colitis.

Therapeutic strategies for patients with ulcerative colitis (UC) are based on patient- and disease-related factors in combination with drug characteristics but fail to predict success in individual patients. A considerable proportion of UC patients do not respond to the biological vedolizumab. Therefore, pretreatment biomarkers for therapeutic efficacy are urgently needed. Mucosal markers related to the integrin-dependent T lymphocyte homing could be potent predictors. We prospectively included 21 biological- and steroid-naive UC patients with moderate-to-severe disease activity planned to escalate therapy to vedolizumab. At week 0, before initiating treatment, colonic biopsy specimens were obtained for immunophenotyping and immunohistochemistry. Clinical and endoscopic disease activity were determined at week 16 after 4 infusions of vedolizumab. In addition, we retrospectively included 5 UC patients who were first treated with anti-tumor necrosis factor α before receiving vedolizumab to compare with biological-naive patients. Abundance of α4β7 on more than 8% of all CD3+ T lymphocytes in colonic biopsies at baseline was predictive for responsiveness to vedolizumab (sensitivity 100%, specificity 100%). The threshold for the proportion of MAdCAM-1+ and PNAd+ of all venules in the biopsies predictive for responsiveness to vedolizumab was ≥2.59% (sensitivity 89%, specificity 100%) and ≥2.41% (sensitivity 61%, specificity 50%), respectively. At week 16, a significant decrease of α4β7+CD3+T lymphocytes was demonstrated in responders (18% [12%-24%] to 8% [3%-9%]; P = .002), while no difference was seen in nonresponders (4% [3%-6%] to 3%; P = .59). UC responders to vedolizumab have a higher percentage of α4β7+CD3+ T lymphocytes and a higher proportion of MAdCAM-1+ venules in colonic biopsies than nonresponders before initiating therapy. Both analyses could be promising predictive biomarkers for therapeutic response and may lead to more patient tailored treatment in the future.

RF09 | PSAT88 Pro-opiomelanocortin (POMC), ACTH and Cortisol Responses to Pediatric Cardiac Surgery

Abstract Introduction In critically ill adults, high plasma free cortisol in face of suppressed plasma ACTH coincides with high plasma pro-opiomelanocortin (POMC), the ACTH precursor (1). Further augmenting the systemic glucocorticoid availability with hydrocortisone treatment further lowered plasma ACTH, while plasma POMC remained unaffected (2). The dynamics of POMC in relation to ACTH and free cortisol prior to intensive care unit (ICU) admission are unknown, as well as the impact hereon of glucocorticoid treatment. Also, elevated plasma POMC concentrations have not yet been confirmed in pediatric ICU (PICU) patients. In pediatric cardiac surgery-induced critical illness, we hypothesized that plasma POMC is elevated and that plasma ACTH transiently rises per-operatively and becomes suppressed once free cortisol has risen on PICU day 1 and 2. In addition, we hypothesized that in patients receiving glucocorticoids per-operatively, plasma ACTH is further suppressed while plasma POMC is unaffected. Methods From 53 children aged 0-36 months, who underwent cardiac surgery and were admitted to the PICU, blood samples were taken prior to surgery (pre-operatively, available samples N=51), during surgery (per-operatively, N=47), on the following morning (PICU day 1, N=40) and the day hereafter (PICU day 2, N=24). Blood samples were also collected from 24 age- and gender-matched healthy children. To investigate the impact of synthetic glucocorticoid treatment on the endogenous plasma hormone concentrations, patients were categorized into steroid-naive (total N=38) and steroid-treated patients (total N=15). Plasma hormone concentrations were quantified with highly-specific ELISA (POMC), RIA (ACTH, cortisol, CBG) or colorimetric assays (albumin). Cross reactivity with synthetic glucocorticoids within the used cortisol RIA is minimal (<0.27% for methylprednisolone, <0.1% for dexamethasone). Free cortisol was estimated with the adapted Coolens’ formula. Results Plasma POMC was increased pre-operatively (p<0.0001) but no longer thereafter (p>0.05), irrespective of steroid treatment. Plasma ACTH in patients was never higher than in healthy children. While in steroid-naive patients, plasma ACTH became suppressed only by PICU day 1 (p<0.0001), steroid-treated patients had already suppressed plasma ACTH per-operatively (p≤0.0001). In steroid-naive patients, plasma free cortisol was increased from per-operatively onwards (p≤0.002), while in steroid-treated patients, plasma free cortisol (endogenous) concentrations always remained comparable to those of healthy children (p>0.05). Conclusion Pre-operatively high plasma POMC, not followed by increased ACTH, suggests a centrally-activated HPA-axis already prior to surgery and an immature pituitary processing of POMC into ACTH. Systemic glucocorticoid availability is elevated from surgery onwards, likely driven by ACTH-independent mechanisms. Further increasing systemic glucocorticoid availability exogenously with glucocorticoid administration accelerates the suppression of plasma ACTH. The long-term impact of early glucocorticoid treatment in critically ill children remains to be investigated. References (1) Téblick A. et al. Critical Care 2021. (2) Téblick A. et al. Endocrinology 2022. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Saturday, June 11, 2022 1:42 p.m. - 1:47 p.m.

Study to evaluate effect of oral mini pulse corticosteroid therapy for unstable vitiligo on hypothalamic pituitary adrenal axis suppression

BackgroundThe treatment of vitiligo is difficult and usually requires prolonged therapy. All exogenous glucocorticoid therapies can lead to the hypothalamic–pituitary–adrenal axis (HPA) suppression. Steroid therapy in the form of an intermittent pulse therapy is a much safer option than daily administration. Very few studies have been carried out to evaluate the effect of oral minipulse prednisolone (OMP) on HPA axis, and there are no concrete guidelines regarding the tapering of steroids after OMP, if needed at all. This study is a pilot study to evaluate the effect of use of OMP on HPA axis suppression in unstable vitiligo. MethodsIt is an observational prospective study approved by the Institutional Ethics Committee (IEC) of institution carried out on 30 patients with unstable vitiligo being initiated on OMP between the ages of 20–50 yrs carried out at a tertiary care hospital of Western Maharashtra for a period of one year. Inclusion criteria was all new cases of unstable vitiligo attending dermatology OPD with patients in the age group 20–50 years. Patients treated with systemic corticosteroids in the last six months, on prolonged topical steroid therapy, patients on any other immunosuppressive therapy, patients having contraindications for exhibiting systemic steroids were excluded from the study. ResultsThirty steroid-naive patients (11 women, 19 men) with a median duration of vitiligo of 10.67 months duration were evaluated. A total of 19 (63.3%) were males and 11 (36.6%) were females with mean age 29.13 years. Serum cortisol levels at baseline, one week, and the end of therapy were 291.1 nmol/L, 288.7 nmol/L, and 304 nmol/L, respectively. Acton Prolongatum (ACTH) stimulated serum cortisol levels at baseline, one week, and the end of therapy were 658.3 nmol/L, 626.1 nmol/L, and 630.1 nmol/L, respectively. Time taken to achieve stability was a mean of 4.41 months post-initiation of OMP in 22/25(73.3%) patients. In 4/30 (13.3%) patients, no stability was achieved at six months of follow-up. ConclusionsThis pilot study has shown that there is no suppression of serum cortisol levels by OMP prednisolone if taken in a weekly dose. OMP steroid therapy is not very effective to achieve a decent level of repigmentation alone; hence, they should be used in combination with other modalities like topical steroids or phototherapy to achieve better repigmentation. The patients did not develop any systemic or cutaneous side effects due to the drug; hence, prednisolone can be considered a safe drug for pulse therapy.

T2-weighted short-tau-inversion-recovery imaging reflects disease activity of cardiac sarcoidosis

ObjectiveWe investigated the diagnostic performance of semi-quantitative hyperintensity on T2-weighted short-tau-inversion-recovery black-blood (T2W-STIR-BB) images in identifying active cardiac sarcoidosis (CS) in patients, and compared it with that of 18F-fluoro-2-deoxyglucose positron...

Short-term dose and duration-dependent glucocorticoid risk for cardiovascular events in glucocorticoid-naive patients with rheumatoid arthritis

ObjectivesRheumatoid arthritis (RA), along with glucocorticoid use, is associated with cardiovascular disease. Cardiovascular safety of glucocorticoids in RA is controversial and may be related to dose and duration of use....

Comparative efficacy of leukotriene modifier and inhaled corticosteroids in the complex treatment of steroid-naive patients with bronchial asthma combined with chronic obstructive pulmonary disease with neutrophilic type of inflammation

The aim: to compare the efficacy and tolerability of the leukotriene modifier and inhaled corticosteroids in combination with long-acting β2-agonist formoterol in steroid-naive patients with asthma combined with COPD with neutrophilic inflammation. Materials and methods. After obtaining the written consent, 30 patients with asthma combined with COPD and a number of blood neutrophils >4000/μl were randomized (1:1): group I – received a fixed combination of budesonide/formoterol 160/4.5 μg/1 inhalation twice daily as a basic therapy; group II – montelukast 1 tab. (10 mg) once daily and inhalation of formoterol 12 mcg/dose twice daily. The duration of therapy was 12 weeks. General clinical methods, asthma control questionnaires, COPD questionnaire, physical tolerance evaluation (6-minute walk test), pulmonary function tests, quality of life assessment were performed to all the patients before and after the treatment course studied. Results. The combination of budesonide/formoterol improved clinical symptoms – significantly (P < 0.05) increased the total ACT score, decreased the average ACQ score, shortness of breath (mMRC scale), COPD symptoms. PFT indices were improved significantly (P < 0.05), bronchoobstruction at the level of large, medium and small bronchi was significantly reduced. Physical tolerance was significantly improved. There were no statistically significant dynamics of the studied indices in patient group II. The patients of both groups showed a tendency to improve their quality of life. In patients of I group, there was a significant decrease in activity limitations and the total SGRQ score. Conclusions. The combination of inhaled corticosteroid/formoterol has proven to be more effective than the leukotriene modifier or formoterol in steroid-naive patients with asthma combined with COPD and neutrophilic inflammation.

Relationship between age and bronchodilator response at diagnosis in adult-onset asthma

BackgroundPossible variation in bronchodilator response (BDR) according to age at the diagnosis of adult-onset asthma is unknown. Our aim was to assess if BDR in FEV1 is related to age at diagnosis of adult-onset asthma and how many subjects fulfill the 400 mL criterion of BDR, the suggested cut-off for asthma-like reversibility in asthma-COPD overlap (ACO).MethodsA total of 1030 patients with adult-onset asthma were included; 245 from SAAS (Seinäjoki Adult Asthma Study, Finland) and 785 from COREA (Cohort for Reality and Evolution of Adult Asthma in Korea) cohorts. BDR in FEV1 at the diagnosis of asthma was assessed. Patients were divided into groups based on age at asthma diagnosis: < 40, 40–59.9, and ≥ 60 years. The cohorts were analyzed separately.ResultsBDR % in FEV1 did not differ between the groups of different age at asthma diagnosis and no correlation between BDR and age was found. Of patients aged ≥40 years, only 18% (SAAS-cohort) and 5% (COREA-cohort) reached the 400 mL BDR in FEV1. After exclusion of possible ACO patients, the results remained similar.ConclusionBy using two large cohorts of steroid-naive patients with asthma, we have shown that BDR at diagnosis of asthma is constant over large age span range, and the limit of 400 mL in BDR in FEV1 is rarely reached.Trial registrationSeinäjoki Adult Asthma Study is registered at ClinicalTrials.gov with identifier number NCT02733016.

Role of hsCRP as a marker in assessing severity of asthma

Asthma is usually characterized by chronic airway inflammation along with respiratory manifestations like, shortness of breath, wheezing, chest tightness and variable expiratory airflow limitation. Studies have indicated increased levels of systemic markers high sensitivity C-reactive protein in patients with bronchial asthma. Assessment of the levels of high sensitivity C-reactive protein in asthmatic patients.It is a comparative-descriptive and observational study, done during the study period April 2014 – June 2015, and the number of asthmatic patients was 80 and 24 healthy controls. High sensitivity C-reactive protein (hsCRP) levels increased in asthmatic patients irrespective of the use of Inhaled corticosteroids. The mean high sensitivity C-reactive protein level of group A (steroid naïve) is 3.9085 which is higher than that of group B (steroid using patients) 2.7575 and healthy controls 0.5138. Although using Inhaled corticosteroids lead to decrease in hsCRP levels, the difference between the means of hsCRP among the two groups A and B was not statistically significant (p=0.093). But when hsCRP levels of group A and group B are compared with the controls, there was high statistical significance (p=0.001). In Pulmonary function test results, the relationship between hsCRP and FEV1 (forced expiratory volume) showed a negative correlation of hs CRP with FEV1%, and it had even more significant negative correlation in patients who are steroid naïve than patients using steroids. Diminished pulmonary function is related with raise serum hsCRP level more in steroid naive patients. Serum hsCRP can be used as one of the indirect parameters for the assessment of degree of severity in the airways manifestation.

Unexpected effects of systemic steroids on the CRSwNP proteome: is protein upregulation more important than inhibition?

Oral steroids, traditionally thought of as immunosuppressive agents that are broad in their immunomodulatory effects, are a mainstay of treatment to reduce disease burden in chronic rhinosinusitis with nasal polyps (CRSwNP). The purpose of this study was to determine how differentially expressed proteins in CRSwNP are affected by oral steroid therapy. Matched exosomal proteomic arrays were quantified using aptamer-based methods in systemic steroid-naive CRSwNP patients before and after a standardized oral prednisone course (n = 12). Previously identified differentially expressed proteins in CRSwNP patients were compared to determine the effect of steroids on expression. Fisher's exact test and t test were applied to normalized protein expression profiles to determine significance. Of 18 proteins previously identified to be highly underexpressed in CRSwNP, 16 (89%) had an average increase after systemic steroid treatment (p < 0.05). Lactoperoxidase, initially present at 9-fold lower concentrations in CRSwNP subjects, increased by 209% after steroid treatment. A similar trend was observed with other proteins of interest, including platelet factor 4 and C-C motif ligand 28. The converse of this steroid effect was not true; of the 53 proteins that are highly overexpressed in CRSwNP, only 22 (42%) decreased in quantity with steroid use. Proteomic analysis of differentially expressed proteins in CRSwNP demonstrates that systemic steroids cause almost uniform upregulation of transcriptionally decreased proteins, whereas the effects of steroids on transcriptionally increased proteins are more heterogeneous. Thus, proteomic analysis may be an effective tool to understand specific therapeutic benefits of steroid use in polyp disease and to create more targeted treatments.

Quantitative MRI as marker of the effectiveness of steroid treatment in patients with Duchenne muscular dystrophy

Due to development of new methods for the treatment of Duchenne muscular dystrophy (DMD), aimed at suppressing inflammatory activity in skeletal muscles, there is a necessity for objective instrumental methods for assessing the effectiveness of the therapy. This method could be selective excitation of the water T2 signal.&#x0D; Aim of the study: to determine the possibility of applying the method of selective excitation of water T2 signal as a quantitative biomarker of the effectiveness of steroid treatment in patients with DMD at different stages of the disease. The study involved 34 DMD boys, who were divided into three groups: ambulant patients taking steroid treatment (n = 14), steroid-naive ambulant patients (n = 10), steroid-naive non-ambulant patients (n = 10) and a control group (n = 10). MRI of the pelvic girdle, thighs and lower legs with multi-slice-multi-echo (MSME) sequences has been done for all subjects. Calculation of the water T2 values has been done by the three-exponential method.&#x0D; Results: There was a significant difference (p 0.01) between the three study groups, the highest inflammatory activity was determined in the steroid-naive patients and signal intensity was 39.4 1.0 ms for the pelvic girdle muscles, 37.3 1.1 ms for the thighs muscles and 38.1 1.8 ms for the legs muscles. Thus, using of the technique of selectively determination of the signal from water on T2 weighted images can be quantitative biomarker of inflammatory activity and the effectiveness of steroid treatment in patients with Duchenne muscular dystrophy in different stages

Relationship between Blood and Induced Sputum Eosinophils, Bronchial Hyperresponsiveness and Reversibility of Airway Obstruction in Mild-to-Moderate Chronic Obstructive Pulmonary Disease

Blood eosinophilia has been proposed as a surrogate marker for airway eosinophilia and as a predictor of treatment response in chronic obstructive pulmonary disease (COPD). The aim of the study was to assess the relationship between blood and sputum eosinophils and to investigate the association between blood and sputum eosinophil count and clinical features of mild-to-moderate COPD. We performed a retrospective analysis of blood and sputum eosinophil count, as well as demographic and lung function data in a cohort of 90 stable, steroid-naive (Global Initiative for Chronic Obstructive Lung Disease 1 or 2) COPD patients and 20 control subjects. Blood and sputum eosinophil count did not correlate both in patients with COPD (r = –0.04 p = 0.705) and in controls (r = 0.05, p = 0.838). Sputum eosinophilia (≥3%) was present in 40% of COPD patients. The median blood eosinophil count in patients with COPD was 180 (interquartile range 90–270)/μL; patients with low blood eosinophils (<180/μL) did not differ from those with high blood eosinophils (≥180/μL) in terms of forced expiratory volume in 1 second, bronchial reversibility or hyperresponsiveness. This was also the case when COPD patients with and without sputum eosinophilia were compared. At the same time, positive bronchial reversibility and positive bronchial hyperresponsiveness were observed in 2 (11%) COPD patients with high blood eosinophils and in 1 (5%) patient with sputum eosinophilia. There was a weak, albeit significant correlation (r = 0.22 p = 0.041) between blood eosinophil count and age in patients with COPD. Peripheral eosinophil count poorly reflects sputum eosinophils and lung function in stable steroid-naive mild-to-moderate COPD patients.

A Dose–Response Study to Examine the Methodology for Demonstrating the Local Therapeutic Equivalence of the Fluticasone Propionate Component of an Orally Inhaled Combination Therapy of Fluticasone Propionate/Salmeterol Dry Powder

Background: Asthma is widely treated using inhaled corticosteroid/long-acting beta-agonist combinations, such as fluticasone propionate/salmeterol (FPS) dry powder inhaler. Some regulators require generic medications to demonstrate local therapeutic equivalence (LTE) for each component of the FPS reference product. Fractional exhaled nitric oxide (FeNO) was developed as a possible LTE endpoint for the fluticasone propionate (FP) component of FPS in a randomized, double-blind, crossover study in steroid-naive asthma patients with elevated FeNO (≥45 parts per billion). Methods: Thirty-four patients received three of five treatments: FPS 100/50 μg once daily (QD), FPS 100/50 μg twice daily (BID), FPS 250/50 μg BID, FPS 500/50 μg BID, or placebo, each for 2 weeks separated by 14-day washout. FeNO was measured on days 1, 2, 3, 5, 7, and 14 of each period, according to American Thoracic Society standards. Results: FPS treatments decreased FeNO compared with placebo, with the largest differentiation between doses noted on day 14; the mean decreases from days 1 to 14 ranged from -46.6% to -64.5% with FPS versus -9.1% with placebo. The dose-response plateaued at 200 μg/day (FPS 100/50 μg BID). Linear regression analysis revealed significant slopes between FPS doses, with the steepest between 100/50 μg QD and 100/50 μg BID (-0.0039, p = 0.020). An estimated sample size (SS) of 160 or 48 patients would be required to demonstrate LTE of generic and FPS reference products (0.80-1.25 and 0.67-1.50 bioequivalence limits, respectively). However, as the slope between BID FPS doses was shallow, a larger SS may be needed if only an approved dose regimen was used. Conclusion: FeNO could be a valid endpoint to determine LTE between the FP component of generic and reference FPS products, but only if QD dosing and wide equivalence limits are included. As QD dosing is not an approved regimen, this approach is unlikely to be acceptable.

Innate immune crosstalk in asthmatic airways: Innate lymphoid cells coordinate polarization of lung macrophages

Recent studies have emphasized the role of innate lymphoid cells (ILCs) in the development of asthma. The involvement of group 2 innate lymphoid cells (ILC2s) in asthma is well studied: however, the participation of other types of ILCs in the development of asthma remains unclear. This study aims to understand the role of various ILCs in patients with asthma, especially their effect on macrophage polarization. Each subset of ILCs and macrophages in induced sputum from 51 steroid-naive patients with asthma and 18 healthy donors was analyzed by using flow cytometry. Alveolar macrophages (AM) were sorted and cocultured with each subset of ILCs to determine whether the polarization of macrophages could be regulated by ILCs. In addition to ILC2s, numbers of group 1 innate lymphoid cells (ILC1s) and group 3 innate lymphoid cells (ILC3s) were increased in induced sputum from asthmatic patients when compared with those in healthy control subjects. The dominance of macrophages in induced sputum was more prominent in asthmatic patients than in healthy control subjects. Apositive correlation between numbers of ILC2s and numbers of M2 macrophages and those of ILC1s/ILC3s and M1 macrophages was observed. Coculture of ILC2s with AMs induced expression of M2 macrophage-related genes, whereas coculture of ILC1s and ILC3s with AMs induced expression of M1 macrophage-related genes through cytokine secretion, as well as cell-cell contact. According to the inflammatory signature, patients with eosinophilic asthma have more ILC2s and M2 macrophages, and those with noneosinophilic asthma have an M1 macrophage-dominant profile. A different subset of ILCs regulates macrophage polarization, contributing to developing the distinct phenotype of asthma.

Children with severe acute asthma admitted to Dutch PICUs: A changing landscape

The number of children requiring pediatric intensive care unit (PICU) admission for severe acute asthma (SAA) around the world has increased.ObjectivesWe investigated whether this trend in SAA PICU admissions is present in the Netherlands.MethodsA multicenter retrospective cohort study across all tertiary care PICUs in the Netherlands. Inclusion criteria were children (2‐18 years) hospitalized for SAA between 2003 and 2013. Data included demographic data, asthma diagnosis, treatment, and mortality.ResultsIn the 11‐year study period 590 children (660 admissions) were admitted to a PICU with a threefold increase in the number of admissions per year over time. The severity of SAA seemed unchanged, based on the first blood gas, length of stay and mortality rate (0.6%). More children received highflow nasal cannula (P < 0.001) and fewer children needed invasive ventilation (P < 0.001). In 58% of the patients the maximal intravenous (IV) salbutamol infusion rate during PICU admission was 1 mcg/kg/min. However, the number of patients treated with IV salbutamol in the referring hospitals increased significantly over time (P = 0.005). The proportion of steroid‐naïve patients increased from 35% to 54% (P = 0.004), with a significant increase in both age groups (2‐4 years [P = 0.026] and 5‐17 years [P = 0.036]).ConclusionsThe number of children requiring PICU admission for SAA in the Netherlands has increased. We speculate that this threefold increase is explained by an increasing number of steroid‐naïve children, in conjunction with a lowered threshold for PICU admission, possibly caused by earlier use of salbutamol IV in the referring hospitals.

Association between (CCTTT)n repeat polymorphism in NOS2 promoter and asthma exacerbations

Association between (CCTTT)n repeat polymorphism in NOS2 promoter and asthma exacerbations

TRPM8 is overexpressed in the respiratory tract of steroid-naive asthma patients

TRPM8 is overexpressed in the respiratory tract of steroid-naive asthma patients

A Phase I Trial of Janus Kinase (JAK) Inhibition with INCB039110 in Acute Graft-Versus-Host Disease (aGVHD)

Background: Corticosteroids are considered standard first-line systemic therapy for patients with aGVHD, but this approach is effective in only approximately half of all cases. For patients who progress or do not respond to corticosteroids, no specific agent has been identified as standard, and regimens are typically selected based on investigator experience and patient co-morbidities. In preclinical models, JAK inhibition has been shown to impair production of cytokines as well as the differentiation and trafficking of T cells implicated in the pathogenesis of aGVHD. Retrospective studies have suggested that JAK1/JAK2 inhibition with ruxolitinib treatment provides clinical benefit in patients with steroid-refractory GVHD (Zeiser et al, Leukemia 2015;29:2062-2068). Herein, we report preliminary safety results from a prospective randomized, parallel-cohort, open-label phase 1 trial evaluating the potent and selective JAK 1 inhibitor INCB039110 in patients with aGVHD.Methods: Male or female patients 18 years or older who underwent their first allo-hematopoietic stem cell transplant (HSCT) from any donor source and developed grades IIB-IVD aGVHD were eligible for the study. Patients were randomized 1:1 to either a 200 or 300 mg oral daily dose of INCB039110 in combination with corticosteroids, and were stratified based on prior treatment status (treatment-naive [TN] versus steroid-refractory [SR]). The primary endpoint of the study was safety and tolerability; secondary endpoints included overall response rate at Days 14, 28, 56, and 100, non-relapse mortality, and pharmacokinetic (PK) evaluations. Patients were assessed through Day 28 for dose-limiting toxicities (DLTs) and response. A Bayesian approach was used for continuous monitoring of DLTs from Days 1-28. Treatment continued until GVHD progression, unacceptable toxicity, or withdrawal from the study. Acute GVHD was graded according to MN-CIBMTR criteria; adverse events (AEs) were graded according to NCICTCAE v 4.03.Results: Between January and June 2016, 31 patients (TN, n=14; SR, n= 17) were randomized. As of July 25, 2016, data were available from 30 patients who received an oral daily dose of 200 mg (n=14) or 300 mg (n=16) INCB039110 in combination with 2 mg/kg methylprednisolone (or equivalent dose of prednisone). The median durations of treatment were 60.8 days and 56.5 days for patients receiving a daily dose of 200 mg and 300 mg INCB039110, respectively. One DLT of Grade 3 thrombocytopenia was reported. The most frequently reported AEs included thrombocytopenia/platelet count decrease (26.7%), diarrhea (23.3%), peripheral edema (20%), fatigue (16.7%), and hyperglycemia (16.7%). Grade 3 or 4 AEs occurred in 77% of patients and with similar frequency across dose groups and included cytomegalovirus infections (n=3), gastrointestinal hemorrhage (n=3), and sepsis (n=3). Five patients had AEs leading to a fatal outcome, including multi-organ failure (n=2), sepsis (n=1), disease progression (n=1), and bibasilar atelectasis, cardiopulmonary arrest, and respiratory distress (n=1); none of the fatal events was attributed to INCB039110. Efficacy and PK evaluations are ongoing and will be updated at the time of presentation.Conclusion: The oral, selective JAK1 inhibitor INCB039110 can be given safely to steroid-naive or steroid-refractory aGVHD patients. The safety profile was generally consistent in both dose groups. Biomarker evaluation, PK, and cellular phenotyping studies are ongoing. The recommended phase 2 dose will be selected and reported based on PK studies and final safety data. DisclosuresSchroeder:Incyte Corporation: Honoraria, Research Funding. Khoury:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jagasia:Incyte Corporation: Research Funding; Therakos: Research Funding; Janssen: Research Funding. Ali:Incyte Corporation: Research Funding. Schiller:Incyte Corporation: Research Funding. Arbushites:Incyte Corporation: Employment, Equity Ownership. Delaite:Incyte Corporation: Employment, Equity Ownership. Yan:Incyte Corporation: Employment, Equity Ownership. Rhein:Incyte Corporation: Employment, Equity Ownership. Perales:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chen:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. DiPersio:Incyte Corporation: Research Funding.

Steroid-induced Deficiency of Mucosal-associated Invariant T Cells in the Chronic Obstructive Pulmonary Disease Lung. Implications for Nontypeable Haemophilus influenzae Infection.

Mucosal-associated invariant T (MAIT) cells are a recently described abundant, proinflammatory T-cell subset with unknown roles in pulmonary immunity. Nontypeable Haemophilus influenzae (NTHi) is the leading bacterial pathogen during chronic obstructive pulmonary disease (COPD) exacerbations and is a plausible target for MAIT cells. To investigate whether MAIT cells respond to NTHi and the effects of inhaled corticosteroids (ICS) on their frequency and function in COPD. Eleven subjects with COPD receiving ICS, 8 steroid-naive subjects with COPD, and 21 healthy control subjects underwent phlebotomy, sputum induction, bronchoalveolar lavage, and endobronchial biopsy. Pulmonary and monocyte-derived macrophages were cultured in vitro with NTHi. Frequencies of Vα7.2+CD161+ MAIT cells, surface expression of the major histocompatibility complex-related protein 1 (MR1), and intracellular IFN-γ expression were measured by flow cytometry. MAIT-cell frequencies were reduced in peripheral blood of ICS-treated subjects with COPD (median 0.38%; interquartile range [IQR], 0.25-0.96) compared with healthy control subjects (1.8%; IQR, 1.4-2.5; P = 0.001) or steroid-naive patients with COPD (1.8%; IQR, 1.2-2.3; P = 0.04). MAIT cells were reduced in bronchial biopsies from subjects with COPD treated with steroids (0.73%; IQR, 0.46-1.3) compared with healthy control subjects (4.0%; IQR, 1.6-5.0; P = 0.02). Coculture of live NTHi increased macrophage surface expression of MR1 and induced IFN-γ from CD4 cells and CD8 cells, but most potently from MAIT cells (median IFN-γ-positive frequencies, 2.9, 8.6, and 27.6%, respectively). In vitro fluticasone and budesonide reduced MR1 surface expression twofold and decreased NTHi-induced IFN-γ secretion eightfold. MAIT cells are deficient in blood and bronchial tissue in steroid-treated, but not steroid-naive, COPD. NTHi constitutes a target for pulmonary MAIT-cell immune responses, which are significantly impaired by corticosteroids.

NIOX VERO: Individualized Asthma Management in Clinical Practice

As we move toward an era of precision medicine, novel biomarkers of disease will enable the identification and personalized treatment of new endotypes. In asthma, fractional exhaled nitric oxide (FeNO) serves as a surrogate marker of airway inflammation that often correlates with the presence of sputum eosinophils. The increase in FeNO is driven by an upregulation of inducible nitric oxide synthase (iNOS) by cytokines, which are released as a result of type-2 airway inflammation. Scientific evidence supports using FeNO in routine clinical practice. In steroid-naive patients and in patients with mild asthma, FeNO levels decrease within days after corticosteroid treatment in a dose-dependent fashion and increase after steroid withdrawal. In difficult asthma, FeNO testing correlates with anti-inflammatory therapy compliance. Assessing adherence by FeNO testing can remove the confrontational aspect of questioning a patient about compliance and change the conversation to one of goal setting and ways to improve disease management. However, the most important aspect of incorporating FeNO in asthma management is the reduction in the risk of exacerbations. In a recent primary care study, reduction of exacerbation rates and improved symptom control without increasing overall inhaled corticosteroid (ICS) use were demonstrated when a FeNO-guided anti-inflammatory treatment algorithm was assessed and compared to the standard care. A truly personalized asthma management approach—showing reduction of exacerbation rates, overall use of ICS and neonatal hospitalizations—was demonstrated when FeNO testing was applied as part of the treatment algorithm that managed asthma during pregnancy. The aim of this article is to describe how FeNO and the NIOX VERO® analyzer can help to optimize diagnosis and treatment choices and to aid in the monitoring and improvement of clinical asthma outcomes in children and adults.