Real-World Effectiveness of Anti-IL-5/5R Therapy in Severe Atopic Eosinophilic Asthma with Fungal Sensitization.

BACKGROUND: Severe asthma with fungal sensitization (SAFS) is a complex clinical phenotype associated with poorly controlled type 2 inflammation and significant morbidity from both the disease itself and a high steroid burden. OBJECTIVE: To assess the effectiveness of biologic therapies targeting eosinophilic inflammation in SAFS. METHODS: We assessed the effectiveness of treatment with mepolizumab or benralizumab in patients with SAFS, and compared outcomes with patients with severe atopic asthma without fungal sensitization and patients with severe nonatopic asthma. Baseline clinical characteristics and clinical outcomes at 48 weeks were evaluated. A subgroup analysis was performed of patients who met the criteria for allergic bronchopulmonary aspergillosis (ABPA) rather than SAFS. RESULTS: A total of 193 patients treated with mepolizumab (n = 63) or benralizumab (n = 130) were included. Patients with SAFS had higher baseline IgE level compared with patients with severe atopic asthma without fungal sensitization and severe nonatopic asthma (733 ± 837 IU/mL vs 338 ± 494 and 142 ± 171, respectively; both P < .001). There were no other significant baseline differences in clinical characteristics between groups. At 48 weeks, there were significant improvements in 6-item asthma control questionnaire score and exacerbation frequency, and reduction in maintenance oral corticosteroid dose across all groups (all P < .05). No significant between-group differences in outcomes were observed at 48 weeks. Patients with ABPA (n = 9) had a significant reduction in exacerbation frequency (P = .013) with treatment. CONCLUSIONS: Treatment with eosinophil-targeting biologics led to improvements in exacerbation frequency, oral corticosteroid requirements, and patient-reported outcomes in patients with SAFS, with a reduction in exacerbations in the subgroup of patients with ABPA. These data highlight the potential clinical utility of targeting eosinophilic inflammation in SAFS and ABPA.

A pragmatic guide to choosing biologic therapies in severe asthma.

There are now several monoclonal antibody (mAb) therapies ("biologics") available to treat severe asthma. Omalizumab is an anti-IgE mAb and is licensed in severe allergic asthma. Current evidence suggests it may decrease exacerbations by augmenting deficient antiviral immune responses in asthma. Like all other biologics, clinical efficacy is greatest in those with elevated T2 biomarkers. Three biologics target the interleukin (IL)-5-eosinophil pathway, including mepolizumab and reslizumab that target IL-5 itself, and benralizumab that targets the IL-5 receptor (IL-5R-α). These drugs all reduce the exacerbation rate in those with raised blood eosinophil counts. Mepolizumab and benralizumab have also demonstrated steroid-sparing efficacy. Reslizumab is the only biologic that is given intravenously rather than by the subcutaneous route. Dupilumab targets the IL-4 receptor and like mepolizumab and benralizumab is effective at reducing exacerbation rate as well as oral corticosteroid requirements. It is also effective for the treatment of nasal polyposis and atopic dermatitis. Tezepelumab is an anti-TSLP (thymic stromal lymphopoietin) mAb that has recently completed phase 3 trials demonstrating significant reductions in exacerbation rate even at lower T2 biomarker thresholds. Many patients with severe asthma qualify for more than one biologic. To date, there are no head-to-head trials to aid physicians in this choice. However, post-hoc analyses have identified certain clinical characteristics that are associated with superior responses to some therapies. The presence of allergic and/or eosinophilic comorbidities, such as atopic dermatitis, nasal polyposis or eosinophilic granulomatosis with polyangiitis, that may additionally benefit by the choice of biologic should also be taken into consideration, as should patient preferences which may include dosing frequency. To date, all biologics have been shown to have excellent safety profiles.

Real-World Effectiveness of Benralizumab in Severe Eosinophilic Asthma.

BACKGROUND: Benralizumab is an IL5-receptor monoclonal antibody licensed for the treatment of severe eosinophilic asthma (SEA). It has demonstrated efficacy in clinical trials in reducing asthma exacerbation rates and maintenance oral corticosteroids (mOCSs). RESEARCH QUESTION: What is the real-world effectiveness of benralizumab and what baseline characteristics are associated with response to therapy? STUDY DESIGN AND METHODS: We assessed outcomes in all SEA patients who began benralizumab treatment at our specialist center. At each dosing visit, exacerbation history, mOCS dose, spirometry, and Asthma Control Questionnaire (ACQ6) and Mini-Asthma Quality of Life Questionnaire (mAQLQ) scores were recorded. Response to treatment was defined as a reduction of ≥ 50% in annualized exacerbation rate (AER) or in mOCS dose after 48 weeks of treatment. Super response was defined as zero exacerbations and no mOCSs for asthma. RESULTS: One hundred thirty patients were included in the analysis. At 48 weeks, a 72.8% reduction in AER was noted, from 4.92 ± 3.35 per year in the year preceding biologic treatment to 1.34 ± 1.71 per year (P < .001), including 57 patients (43.8%) who were exacerbation-free with benralizumab. In those receiving mOCSs (n = 74 [56.9%]), the median daily prednisolone dose fell from 10 mg (interquartile range, 5-20 mg) to 0 mg (interquartile range, 0-5 mg; P < .001), and 38 of 74 patients (51.4%) were able to discontinue mOCS therapy. Clinically and statistically significant improvements were found in ACQ6 scores, mAQLQ scores, and FEV1. Overall, 51 patients (39%) met the super responder definition and 112 patients (86%) met the responder definition. The optimal regression model of super responders vs other responders included baseline characteristics associated with a strongly eosinophilic phenotype and less severe disease. Eighteen patients (13.8%) were nonresponders to benralizumab. Evidence of chronic airway infection was observed in 6 of 18 patients, and an increase in the blood eosinophil count consistent with the development of anti-drug antibodies was observed in 5 of 18 patients. INTERPRETATION: In a large real-world SEA cohort, benralizumab led to significant improvements in all clinical outcome measures. A lack of response was seen in a minority of patients and should be a focus for future investigation.

Biologic treatment options for severe asthma.

Asthma is a common condition that causes episodic expiratory airflow limitation due to bronchial smooth muscle constriction and airways inflammation resulting in increased respiratory symptoms and acute asthma exacerbations. Patients with severe asthma have relied on either recurrent courses or daily use of oral corticosteroids (OCS) to control their disease. However a high level of OCS exposure is associated with significant morbidity and mortality. In recent years the elucidation of the role of T2 inflammation underpinning asthma pathogenesis has led to the development of monoclonal antibody (mAb) therapies targeting this pathway. Established therapies now include omalizumab targeting IgE, mepolizumab and reslizumab targeting IL-5, benralizumab targeting the IL-5R and dupilumab targeting IL-4R. For many patients these therapies have been transformative and their use has additionally advanced our understanding of the immunology that underpins the disease. This article reviews the biologic therapies currently available for the treatment of severe asthma.

Osteoporosis in multiple sclerosis.

Fractures resulting from osteoporosis are a major cause of morbidity and mortality in the developed world. People with multiple sclerosis experience reduced mobility and are susceptible to falls. Glucocorticoid use and reduced mobility are known risk factors for osteoporosis. This paper is a review of osteoporosis in people with multiple sclerosis, looking at its prevalence, risk factors and possible mechanisms. We also review management guidelines for osteoporosis in the general population and use these to propose guidelines for osteoporosis management amongst multiple sclerosis patients. A number of studies have examined the incidence of reduced bone mineral density amongst people with multiple sclerosis; the majority provide convincing evidence that bone mineral density is significantly reduced in multiple sclerosis patients. The most significant risk factors appear to arise from the chronic disease process of multiple sclerosis and not from glucocorticoid use. There are currently no guidelines or consensus as how best to treat osteoporosis amongst multiple sclerosis patients despite their being at an increased risk. We propose an algorithm for the screening and treatment of osteoporosis in people with multiple sclerosis.