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Background: Although estimates of suboptimal adherence to oral corticosteroids in asthma range from 30% to 50%, no ideal method for measurement exists; the impact of poor adherence in severe asthma is likely to be particularly high. Research Questions: What is the prevalence of suboptimal adherence detected by self-reporting and direct measures? Is suboptimal adherence associated with disease activity? Study Design and Methods: Data were included from individuals with severe asthma taking part in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes) study and prescribed daily oral corticosteroids. Participants completed the Medication Adherence Report Scale, a five-item questionnaire used to grade adherence on a scale from 1 to 5, and provided a urine sample for analysis of prednisolone and metabolites by liquid chromatography-mass spectrometry. Results: Data from 166 participants were included in this study: mean (SD) age, 54.2 (± 11.9) years; FEV 1, 65.1% (± 20.5%) predicted; female, 58%; 37% completing the Medication Adherence Report Scale reported suboptimal adherence; and 43% with urinary corticosteroid data did not have detectable prednisolone or metabolites in their urine. Good adherence by both methods was detected in 49 of the 142 (35%) of participants in whom both methods were performed; adherence detection did not match between methods in 53%. Self-reported high adherers had better asthma control and quality of life, whereas directly measured high adherers had lower blood eosinophil levels. Interpretation: Low adherence is a common problem in severe asthma, whether measured directly or self-reported. We report poor agreement between the two methods, suggesting some disassociation between self-assessment of medication adherence and regular oral corticosteroid use, which suggests that each approach may provide complementary information in clinical practice.

Human type 2 cytotoxic T (Tc2) cells are enriched in severe eosinophilic asthma and can contribute to airway eosinophilia. PGD2 and its receptor PGD2 receptor 2 (DP2) play important roles in Tc2 cell activation, including migration, cytokine production, and survival. In this study, we revealed novel, to our knowledge, functions of the PGD2/DP2 axis in Tc2 cells to induce tissue-remodeling effects and IgE-independent PGD2 autocrine production. PGD2 upregulated the expression of tissue-remodeling genes in Tc2 cells that enhanced the fibroblast proliferation and protein production required for tissue repair and myofibroblast differentiation. PGD2 stimulated Tc2 cells to produce PGD2 using the routine PGD2 synthesis pathway, which also contributed to TCR-dependent PGD2 production in Tc2 cells. Using fevipiprant, a specific DP2 antagonist, we demonstrated that competitive inhibition of DP2 not only completely blocked the cell migration, adhesion, proinflammatory cytokine production, and survival of Tc2 cells triggered by PGD2 but also attenuated the tissue-remodeling effects and autocrine/paracrine PGD2 production in Tc2 induced by PGD2 and other stimulators. These findings further confirmed the anti-inflammatory effect of fevipiprant and provided a better understanding of the role of Tc2 cells in the pathogenesis of asthma.

BackgroundProstaglandin D2(PGD2) signaling via prostaglandin D2receptor 2 (DP2) contributes to atopic and non-atopic asthma. Inhibiting DP2has shown therapeutic benefit in certain subsets of asthma patients, improving eosinophilic airway inflammation. PGD2metabolites prolong the inflammatory response in asthmatic patients via DP2signaling. The role of PGD2metabolites on eosinophil and ILC2 activity is not fully understood.MethodsEosinophils and ILC2s were isolated from peripheral blood of atopic asthmatic patients. Eosinophil shape change, ILC2 migration and IL-5/IL-13 cytokine secretion were measured after stimulation with seven PGD2metabolites in presence or absence of the selective DP2antagonist fevipiprant.ResultsSelected metabolites induced eosinophil shape change with similar nanomolar potencies except for 9α,11β-PGF2. Maximal values in forward scatter of eosinophils were comparable between metabolites. ILC2s migrated dose-dependently in the presence of selected metabolites except for 9α,11β-PGF2with EC50values ranging from 17.4 to 91.7 nM. Compared to PGD2, the absolute cell migration was enhanced in the presence of Δ12-PGD2, 15-deoxy-Δ12,14-PGD2, PGJ2, Δ12-PGJ2and 15-deoxy-Δ12,14-PGJ2. ILC2 cytokine production was dose dependent as well but with an average sixfold reduced potency compared to cell migration (IL-5 range 108.1 to 526.9 nM, IL-13 range: 125.2 to 788.3 nM). Compared to PGD2, the absolute cytokine secretion was reduced in the presence of most metabolites. Fevipiprant dose-dependently inhibited eosinophil shape change, ILC2 migration and ILC2 cytokine secretion with (sub)-nanomolar potencies.ConclusionProstaglandin D2metabolites initiate ILC2 migration and IL-5 and IL-13 cytokine secretion in a DP2dependent manner. Our data indicate that metabolites may be important for in vivo eosinophil activation and ILC2 migration and to a lesser extent for ILC2 cytokine secretion.

Additional file 1: Table S1. Detailed information on flow cytometric antibodies used for cell sorting of ILC2s. Table S2. Calculated agonist EC70 values for PGD2 and seven selected PGD2 metabolites. Table S3. Characteristics of study subjects. All subjects had a history of allergic asthma since at least 12 months. BMI had to be between 19 to 32 kg/ m2. Figure S1. Eosinophil shape change induced by PGD2, DK-PGD2, ∆12-PGD2, 15-deoxy-∆12,14-PGD2, PGJ2, 9a,11b-PGF2, ∆12-PGJ2 and 15-deoxy-∆12,14-PGJ2. Granulocytes were isolated from whole blood of asthmatic patients and were incubated with increasing concentrations of metabolites, n=3, 9α,11β-PGF2: n=2. The mean fluorescence values of the forward scatter were determined by flow cytometry and the percentage of shape change above basal was calculated. Values are given as mean ± SD. Figure S2. Concentration of IL-5 cytokine secretion of ILC2s in the presence of ascending concentrations of PGD2 and selected metabolites, n=3. Values are given for three different subjects (circle, square and triangle). Figure S3. Concentration of IL-13 cytokine secretion of ILC2s in the presence of ascending concentrations of PGD2 and selected metabolites, n=3. Values are given for three different subjects (circle, square and triangle).

Key Points Multiple proinflammatory effects of Tc2 cells are inhibited by DP2 antagonism. Tissue-remodeling functions of Tc2 cells are attenuated by DP2 antagonism. Autocrine/paracrine PGD2 production in Tc2 cells is reduced by DP2 antagonism., Human type 2 cytotoxic T (Tc2) cells are enriched in severe eosinophilic asthma and can contribute to airway eosinophilia. PGD2 and its receptor PGD2 receptor 2 (DP2) play important roles in Tc2 cell activation, including migration, cytokine production, and survival. In this study, we revealed novel, to our knowledge, functions of the PGD2/DP2 axis in Tc2 cells to induce tissue-remodeling effects and IgE-independent PGD2 autocrine production. PGD2 upregulated the expression of tissue-remodeling genes in Tc2 cells that enhanced the fibroblast proliferation and protein production required for tissue repair and myofibroblast differentiation. PGD2 stimulated Tc2 cells to produce PGD2 using the routine PGD2 synthesis pathway, which also contributed to TCR-dependent PGD2 production in Tc2 cells. Using fevipiprant, a specific DP2 antagonist, we demonstrated that competitive inhibition of DP2 not only completely blocked the cell migration, adhesion, proinflammatory cytokine production, and survival of Tc2 cells triggered by PGD2 but also attenuated the tissue-remodeling effects and autocrine/paracrine PGD2 production in Tc2 induced by PGD2 and other stimulators. These findings further confirmed the anti-inflammatory effect of fevipiprant and provided a better understanding of the role of Tc2 cells in the pathogenesis of asthma.

This drug-drug interaction (DDI) study determined the effect of cyclosporine, an inhibitor of OATP1B3 and P-gp, on the pharmacokinetics (PK) of fevipiprant, an oral, highly selective, competitive antagonist of the prostaglandin D2 receptor 2 and a substrate of the two transporters. The concomitant administration of an intravenous (IV) microdose of stable isotope-labeled fevipiprant provided the absolute bioavailability of fevipiprant, as well as mechanistic insights in its PK and sensitivity to drug interactions. Liquid chromatography-mass spectrometry/mass spectrometry was used to measure plasma and urine concentrations. Geometric mean ratios (90% CI) for oral fevipiprant with or without cyclosporine were: for Cmax, 3.02 (2.38, 3.82); for AUClast, 2.50 (2.17, 2.88); and for AUCinf, 2.35 (1.99, 2.77). The geometric mean ratios (90% CI) for fevipiprant IV microdose with or without cyclosporine were: for Cmax, 1.04 (0.86, 1.25); for AUClast, 2.04 (1.83, 2.28) and for AUCinf, 1.95 (1.76, 2.16). The absolute bioavailability for fevipiprant was approximately 0.3-0.4 in the absence and 0.5 in the presence of cyclosporine. The IV microdose allowed differentiation between systemic and pre-systemic effects of cyclosporine on fevipiprant, demonstrating a small (approximately 1.2-fold) pre-systemic effect of cyclosporine and a larger (approximately 2-fold) effect on systemic elimination of fevipiprant. Uptake by OATP1B3 appears to be the rate-limiting step in the hepatic elimination of fevipiprant while P-gp does not have a relevant effect on oral absorption. SIGNIFICANCE STATEMENT The drug interaction investigated here with cyclosporine, an inhibitor of several drug transporters, provides a refined quantitative understanding of the role of active transport processes in liver and intestine for the absorption and elimination of fevipiprant, as well as the basis to assess the need for dose adjustment in the presence of transporter inhibitors. The applied IV microdose approach presents a strategy to maximize learnings from a trial, limit the number and duration of clinical trials, and enhance mechanistic DDI understanding.

Introduction: Secukinumab, a fully human monoclonal antibody that directly inhibits interleukin-17A, has demonstrated robust efficacy in the treatment of moderate to severe psoriasis (PsO), psoriatic arthritis (PsA) and ankylosing spondylitis (AS), with a rapid onset of action, sustained long-term clinical responses and a consistently favourable safety profile across phase 3 trials. Here, we report the clinical data at enrolment from SERENA, designed to investigate the real-world use of secukinumab across all three indications. Methods: SERENA is an ongoing, longitudinal, observational study conducted at 438 sites across Europe in patients with moderate to severe plaque PsO, active PsA or active AS. Patients should have received at least 16 weeks of secukinumab treatment before enrolment in the study. Results: Overall 2800 patients were included in the safety set; patients with PsA (N = 541) were older than patients with PsO (N = 1799) and patients with AS (N = 460); patients with PsO had a higher mean body weight than patients with PsA and patients with AS; and patients with PsO and patients with AS were predominantly male. Time since diagnosis was longer in patients with PsO compared with patients with PsA and patients with AS, and about 40% of patients were either current or former smokers. The proportion of obese patients (body mass index ≥ 30 kg/m2) was similar across indications. Patients were treated with secukinumab for a mean duration of 1 year prior to enrolment (range 0.89–1.04). The percentages of patients with prior biologics exposure were 31.5% PsO, 59.7% PsA and 55% AS. The percentages of patients prescribed secukinumab monotherapy were 75% (n = 1349) in PsO, 48.2% (n = 261) in PsA and 48.9% (n = 225) in AS groups. Conclusion: Baseline demographics of the study population are consistent with existing literature. This large observational study across all secukinumab indications will provide valuable information on the long-term effectiveness and safety of secukinumab in the real-world setting. © 2020, The Author(s).

Introduction and objectives. Chronic spontaneous urticaria (CSU), including severe and treatment-refractory CSU, shows a strong response to omalizumab, a humanized recombinant monoclonal anti-IgE antibody. The effect of omalizumab on gene expression was assessed in skin biopsies from CSU patients enrolled in a double-blind placebo-controlled study (ClinicalTrials.gov Identifier: NCT01599637). Methods. CSU patients (18-75 years) were randomized to either 300 mg omalizumab (n=20) or placebo (n=10) administered s.c. every 4 weeks for 12 weeks. Lesional and non-lesional skin biopsies were collected from the same body area of consenting subjects and assessed at baseline and on Day 85. Skin biopsies from the same area of 10 untreated healthy volunteers (HV) were also processed as reference. Gene expression data were generated using Affymetrix HG-U133plus2.0 microarrays. Statistical analyses were performed using R packages. In brief, after normalization, low-intensity transcripts (i.e. probesets with intensities less than 100 in ≥50% of the samples) were filtered out. To identify transcriptional changes, linear models were constructed taking into account the type of biopsy (lesional or non-lesional), the study visit and the treatment for each patient. Thresholds for statistical significance and minimal fold change (FC) were defined as P-value ≤0.05 (no multiple testing correction) and absolute FC ≥1.5, respectively. Results. At baseline, 63 transcripts were differentially expressed between lesional and non-lesional skin. Two thirds of this lesional signature was also differentially expressed between lesional and HV skin. Upon treatment with omalizumab, over 75% of this lesional signature changed to reflect non-lesional skin expression levels (different to placebo, P-value 16). Conclusions. Omalizumab, in treatment responders, reverted transcriptional signatures associated with the CSU lesion phenotype to reflect non-lesional/HV expression levels. This result is consistent with observed omalizumab-mediated clinical improvement observed in patients with CSU.

Asthma is characterised by chronic airway inflammation, airway obstruction and hyper-responsiveness. The inflammatory cascade in asthma comprises a complex interplay of genetic factors, the airway epithelium, and dysregulation of the immune response. Prostaglandin D2 (PGD2) is a lipid mediator, predominantly released from mast cells, but also by other immune cells such as TH2 cells and dendritic cells, which plays a significant role in the pathophysiology of asthma. PGD2 mainly exerts its biological functions via two G-protein-coupled receptors, the PGD2 receptor 1 (DP1) and 2 (DP2). The DP2 receptor is mainly expressed by the key cells involved in type 2 immune responses, including TH2 cells, type 2 innate lymphoid cells and eosinophils. The DP2 receptor pathway is a novel and important therapeutic target for asthma, because increased PGD2 production induces significant inflammatory cell chemotaxis and degranulation via its interaction with the DP2 receptor. This interaction has serious consequences in the pulmonary milieu, including the release of pro-inflammatory cytokines and harmful cationic proteases, leading to tissue remodelling, mucus production, structural damage, and compromised lung function. This review will discuss the importance of the DP2 receptor pathway and the current understanding of its role in asthma.