The future of allergic rhinitis management : a partnership between health care professionals and patients

Peer reviewe

Real-life biomarker response to anti-IL5 and anti-IgE therapies in severe asthma patients

Funding: This study was conducted by the Observational and Pragmatic Research Institute (OPRI) Pte Ltd and was partially funded by Optimum Patient Care Global and AstraZeneca Ltd. No funding was received by OPRI for its contribution.Peer reviewedPostprin

Association between pre-biologic T2-biomaker combinations and response to biologics in patients with severe asthma

Funding This study was conducted by the Observational and Pragmatic Research Institute (OPRI) Pte Ltd and was partially funded by Optimum Patient Care Global (OPCG) and AstraZeneca Ltd. No funding was received by the OPRI for its contribution. The International Severe Asthma Registry (ISAR) is operated by OPCG and co-funded by OPCG and AstraZenecaPeer reviewe

The function of the signaling protein Ras guanine releasing protein 4 (RasGRP4) in human mast cells

Mast cells have been implicated in the pathogenesis of both atopic and non-atopic asthma. Rasguanine nucleotide-releasing protein 4 (RasGRP4) is a mast cell-restricted guanine nucleotideexchange factor and diacylglycerol (DAG)/ phorbol ester receptor whose function has not beendeduced. RT-PCR analysis of 40 asthmatic patients and 40 non-asthmatic controls demonstrated ahigher hRasGRP4 mRNA expression in a subgroup of the asthmatics. A RasGRP4-defective variantof the human mast cell line HMC-1 was used to create stable clones expressing green fluorescentprotein-labeled human RasGRP4 for monitoring the movement of this signaling protein inside mastcells before and after exposure to phorbol-12-myristate 13-acetate (PMA) and for evaluating theprotein’s ability to control the development, phenotype, and function of mast cells.Transcript-profiling approaches revealed hRasGRP4 constitutively regulates the expression ofnumerous genes in the HMC-1 cell line. For example, expression of hRasGRP4 in HMC-1 cellssubstantially decreased GATA-1 levels without altering GATA-2 levels, suggesting that hRasGRP4regulates mast cell commitment of multipotential progenitors in part by controlling the intracellularlevels of at least one lineage-dependent transcription factor for hematopoietic cells. hRasGRP4resided primarily in the cytosol before HMC-1 cells were stimulated with PMA. After exposure toPMA, hRasGRP4 translocated to the inner leaflet of the cell’s plasma membrane and then toperinuclear and Golgi compartments. Extracellular signal-regulated kinases 1 and 2 were activatedduring this translocation process, and the PMA-treated cells transiently increased their expression ofthe transcripts encoding the interleukin 13 receptor IL-13Rá2 and numerous other proteins.The accumulated data in our mast cell model suggest hRasGRP4 translocates to various intracellularcompartments via its DAG/PMA-binding domain to regulate those signaling pathways that allow mastcells to respond quickly to changes in their tissue microenvironments

Biochemical and Functional Characterization of Human Transmembrane Tryptase(TMT)Ttryptase g.

Transmembrane tryptase (TMT)/tryptase γ is a membrane-bound serine protease stored in the secretory granules of human and mouse lung mast cells (MCs). We now show that TMT reaches the external face of the plasma membrane when MCs are induced to degranul

Severe asthma assessment, management and the organisation of care in Australia and New Zealand: expert forum roundtable meetings

Severe asthma imposes a significant burden on individuals, families and the healthcare system. Treatment is complex, due to disease heterogeneity, comorbidities and complexity in care pathways. New approaches and treatments improve health outcomes for people with severe asthma. However, emerging multidimensional and targeted treatment strategies require a reorganisation of asthma care. Consensus is required on how reorganisation should occur and what areas require further research. The Centre of Excellence in Severe Asthma convened 3 forums between 2015 and 2018, hosting experts from Australia, New Zealand and the UK. The forums were complemented by a survey of clinicians involved in the management of people with severe asthma. We sought to 1) identify areas of consensus among experts, 2) define activities and resources required for the implementation of findings into practice and 3) identify specific priority areas for future research. Discussions identified areas of unmet need including assessment and diagnosis of severe asthma, models of care and treatment pathways, add-on treatment approaches and patient perspectives. We recommend development of education and training activities, clinical resources and standards of care documents, increased stakeholder engagement and public awareness campaigns and improved access to infrastructure and funding. Further, we propose specific future research to inform clinical decision-making and develop novel therapies. A concerted effort is required from all stakeholders (including patients, healthcare professionals and organisations and government) to integrate new evidence-based practices into clinical care and to advance research to resolve questions relevant to improving outcomes for people with severe asthma. This article is protected by copyright. All rights reserved

Mepolizumab effectiveness and identification of super-responders in severe asthma

Severe asthma is a high-burden disease. Real-world data on mepolizumab in patients with severe eosinophilic asthma is needed to assess whether the data from randomised controlled trials are applicable in a broader population.The Australian Mepolizumab Registry (AMR) was established with an aim to assess the use, effectiveness and safety of mepolizumab for severe eosinophilic asthma in Australia.Patients (n=309) with severe eosinophilic asthma (median age 60 years, 58% female) commenced mepolizumab. They had poor symptom control (median Asthma Control Questionnaire (ACQ)-5 score of 3.4), frequent exacerbations (median three courses of oral corticosteroids (OCS) in the previous 12 months), and 47% required daily OCS. Median baseline peripheral blood eosinophil level was 590 cells·µL-1 Comorbidities were common: allergic rhinitis 63%, gastro-oesophageal reflux disease 52%, obesity 46%, nasal polyps 34%.Mepolizumab treatment reduced exacerbations requiring OCS compared with the previous year (annualised rate ratio 0.34 (95% CI 0.29-0.41);

Mepolizumab and oral corticosteroid stewardship : data from the Australian Mepolizumab Registry

Background: Oral corticosteroids (OCS) carry serious health risks. Innovative treatment options are required to reduce excessive exposure and promote OCS stewardship. Objectives: This study evaluated the trajectories of OCS exposure (prednisolone-equivalent) in patients with severe eosinophilic asthma before and after starting mepolizumab and the predictors of becoming OCS free after 6 months of mepolizumab therapy. Methods: This real-world observational study included 309 patients from the Australian Mepolizumab Registry who were followed up for 1 year (n = 225). Results: Patients had a median age of 60 (interquartile range: 50, 68) years, and 58% were female. At baseline, 48% used maintenance OCS, 96% had ≥1 OCS burst, and 68% had received ≥1 g of OCS in the previous year. After commencing mepolizumab, only 55% of those initially on maintenance OCS remained on this treatment by 12 months. Maintenance OCS dose reduced from median 10 (5.0, 12.5) mg/day at baseline to 2 (0, 7.0) mg/day at 12 months (P < .001). Likewise, proportions of patients receiving OCS bursts in the previous year reduced from 96% at baseline to 50% at 12 months (P < .001). Overall, 137 (48%) patients required OCS (maintenance/burst) after 6 months' mepolizumab therapy. Becoming OCS free was predicted by a lower body mass index (odds ratio: 0.925; 95% confidence interval: 0.872-0.981), late-onset asthma (1.027; 1.006-1.048), a lower Asthma Control Test score (1.111; 0.011-1.220), and not receiving maintenance OCS therapy at baseline (0.095; 0.040-0.227). Conclusion: Mepolizumab led to a significant and sustained reduction in OCS dependence in patients with severe eosinophilic asthma. This study supports the OCS-sparing effect of mepolizumab and highlights the pivotal role of mepolizumab in OCS stewardship initiatives