An international consensus on the use of asthma biologics in pregnancy.

Uncontrolled asthma is associated with an increased risk of adverse perinatal outcomes. Asthma biologics reduce exacerbation frequency, are steroid sparing, and improve quality of life in people with severe asthma. However, evidence for the use and safety of asthma biologics during pregnancy is scarce, largely because pregnant women were excluded from clinical trials. To help to support clinical teams, we conducted an international modified Delphi study. 141 panellists from 32 countries who were involved in the care of people with severe asthma completed two rounds of online surveys covering key areas surrounding the use of asthma biologics in pregnancy. The results from this international Delphi study emphasise risk versus benefit discussions and shared clinical decision making, with consensus among panellists that asthma biologics can be used during conception and throughout pregnancy, initiated during pregnancy in line with prescribing criteria for non-pregnant people, and initiated or continued during breastfeeding. Collating data through international registries remains essential to inform clinical guidelines.

How Does Mild Asthma Differ Phenotypically from Difficult-to-Treat Asthma?

Background: Despite most of the asthma population having mild disease, the mild asthma phenotype is poorly understood. Here, we aim to address this gap in knowledge by extensively characterising the mild asthma phenotype and comparing this with difficult-to-treat asthma. Methods: We assessed two real-world adult cohorts from the South of England using an identical methodology: the Wessex AsThma CoHort of difficult asthma (WATCH) (n=498) and a mild asthma cohort from the comparator arm of the Epigenetics Of Severe Asthma (EOSA) study (n=67). Data acquisition included detailed clinical, health and disease-related questionnaires, anthropometry, allergy and lung function testing, plus biological samples (blood and sputum) in a subset. Results: Mild asthma is predominantly early-onset and is associated with type-2 (T2) inflammation (atopy, raised fractional exhaled nitric oxide (FeNO), blood/sputum eosinophilia) plus preserved lung function. A high prevalence of comorbidities and multimorbidity was observed in mild asthma, particularly depression (58.2%) and anxiety (56.7%). In comparison to difficult asthma, mild disease showed similar female predominance (>60%), T2-high inflammation and atopy prevalence, but lower peripheral blood/airway neutrophil counts and preserved lung function. Mild asthma was also associated with a greater prevalence of current smokers (20.9%). A multi-component T2-high inflammatory measure was comparable between the cohorts; T2-high status 88.1% in mild asthma and 93.5% in difficult asthma. Conclusion: Phenotypic characterisation of mild asthma identified early-onset disease with high prevalence of current smokers, T2-high inflammation and significant multimorbidity burden. Early comprehensive assessment of mild asthma patients could help prevent potential later progression to more complex severe disease.

Constitutive Activation of Natural Killer Cells in Primary Biliary Cholangitis.

Natural killer (NK) cells are innate immune cells that interface with the adaptive immune system to generate a pro-inflammatory immune environment. Primary Biliary Cholangitis (PBC) is a hepatic autoimmune disorder with extrahepatic associations including systemic sclerosis, Sjogren's syndrome and thyroiditis. Immunogenetic studies have identified polymorphisms of the IL-12/STAT4 pathway as being associated with PBC. As this pathway is important for NK cell function we investigated NK cells in PBC. Circulating NK cells from individuals with PBC were constitutively activated, with higher levels of CD49a and the liver-homing marker, CXCR6, compared to participants with non-autoimmune chronic liver disease and healthy controls. Stimulation with minimal amounts of IL-12 (0.005 ng/ml) led to significant upregulation of CXCR6 (p < 0.005), and enhanced IFNγ production (p < 0.02) on NK cells from PBC patients compared to individuals with non-autoimmune chronic liver disease, indicating dysregulation of the IL-12/STAT4 axis. In RNAseq studies, resting NK cells from PBC patients had a constitutively activated transcriptional profile and upregulation of genes associated with IL-12/STAT4 signaling and metabolic reprogramming. Consistent with these findings, resting NK cells from PBC patients expressed higher levels of pSTAT4 compared to control groups (p < 0.001 vs. healthy controls and p < 0.05 vs. liver disease controls). In conclusion NK cells in PBC are sensitive to minute quantities of IL-12 and have a "primed" phenotype. We therefore propose that peripheral priming of NK cells to express tissue-homing markers may contribute to the pathophysiology of PBC.