Adherence to corticosteroids and clinical outcomes in mepolizumab therapy for severe asthma.

INTRODUCTION: Inhaled corticosteroids (ICS) achieve disease control in the majority of asthmatic patients, although adherence to prescribed ICS is often poor. Patients with severe eosinophilic asthma may require treatment with oral corticosteroids (OCS) and/or biologic agents such as mepolizumab. It is unknown if ICS adherence changes on, or alters clinical response to, biologic therapy. METHODS: We examined ICS adherence and clinical outcomes in OCS-dependent severe eosinophilic asthma patients who completed 1 year of mepolizumab therapy. The ICS medicines possession ratio (MPR) was calculated (the number of doses of ICS issued on prescription/expected number) for the year before and the year after biologic initiation. Good adherence was defined as MPR >0.75, intermediate 0.74-0.51 and poor <0.5. We examined outcomes after 12 months of biologic therapy, including OCS reduction and annualised exacerbation rate (AER), stratified by adherence to ICS on mepolizumab. RESULTS: Out of 109 patients commencing mepolizumab, 91 who had completed 12 months of treatment were included in the final analysis. While receiving mepolizumab, 68% had good ICS adherence, with 16 (18%) having poor ICS adherence. ICS use within the cohort remained similar before (MPR 0.81±0.32) and during mepolizumab treatment (0.82±0.32; p=0.78). Patients with good adherence had greater reductions in OCS dose (median (interquartile range) OCS reduction 100 (74-100)% versus 60 (27-100)%; p=0.031) and exacerbations (AER change -2.1±3.1 versus 0.3±2.5; p=0.011) than those with poor adherence. Good ICS adherence predicted the likelihood of stopping maintenance OCS (adjusted OR 3.19, 95% CI 1.02-9.94; p=0.045). CONCLUSION: ICS nonadherence is common in severe eosinophilic asthma patients receiving mepolizumab, and is associated with a lesser reduction in OCS requirements and AER.

Distinct endotypes of steroid-resistant asthma characterized by IL-17A(high) and IFN-γ(high) immunophenotypes: Potential benefits of calcitriol.

BACKGROUND: A small population of patients with severe asthma does not respond to glucocorticoids (steroid resistant [SR]). They have high morbidity, highlighting an urgent need for strategies to enhance glucocorticoid responsiveness. OBJECTIVE: We investigated the immunologic differences between steroid-sensitive (SS) and SR asthmatic patients and the effect on immunophenotype of oral calcitriol treatment because it has been previously shown to beneficially modulate the clinical response to glucocorticoids in patients with SR asthma. METHODS: CD8-depleted PBMCs were isolated from 12 patients with SS and 23 patients with SR asthma and cultured for 7 days with anti-CD3 and IL-2 with or without dexamethasone. Cytokine production was assessed in supernatants by using the Cytometric Bead Array. Patients with SR asthma were subsequently randomized to oral calcitriol or placebo therapy, and identical studies were repeated. RESULTS: Patients with SR asthma produced significantly increased IL-17A and IFN-γ levels compared with those in patients with SS asthma, although it was evident that cells from individual patients might overproduce one or the other of these cytokines. Production of IL-17A was inversely and production of IL-13 was positively associated with the clinical response to prednisolone. Oral calcitriol, compared with placebo, therapy of the patients with SR asthma significantly improved dexamethasone-induced IL-10 production in vitro while suppressing dexamethasone-induced IL-17A production. This effect mirrored the previously demonstrated improvement in clinical response to oral glucocorticoids in calcitriol-treated patients with SR asthma. CONCLUSIONS: IL-17A(high) and IFN-γ(high) immunophenotypes exist in patients with SR asthma. These data identify immunologic pathways that likely underpin the beneficial clinical effects of calcitriol in patients with SR asthma by directing the SR cytokine profile toward a more SS immune phenotype, suggesting strategies for identifying vitamin D responder immunophenotypes.

Enhanced production of IL-17A in patients with severe asthma is inhibited by 1α,25-dihydroxyvitamin D3 in a glucocorticoid-independent fashion.

BACKGROUND: TH17 cells are proposed to play a role in the pathology of asthma, including steroid-resistant (SR) disease. We previously identified a steroid-enhancing function of vitamin D in patients with SR asthma in restoring the impaired response to steroids for production of the anti-inflammatory cytokine IL-10. OBJECTIVE: We sought to investigate the production of the TH17-associated cytokines IL-17A and IL-22 in culture in patients with moderate-to-severe asthma defined on the basis of their clinical response to steroids and the susceptibility of this response to inhibition by steroids and the active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25[OH]2D3). METHODS: PBMCs were stimulated in culture with or without dexamethasone and 1,25(OH)2D3. A cytometric bead array, ELISA, and intracellular cytokine staining were used to assess cytokine production. The role of CD39 in inhibition of the TH17 response was studied by using quantitative real-time PCR, flow cytometry, and addition of the antagonist POM-1 to culture. RESULTS: Asthmatic patients synthesized much higher levels of IL-17A and IL-22 than nonasthmatic control subjects, with patients with SR asthma expressing the highest levels of IL-17A. Glucocorticoids did not inhibit IL-17A cytokine expression in patients and enhanced production in cultures from control subjects. Treatment with 1,25(OH)2D3 with or without dexamethasone significantly reduced both IL-17A and IL-22 levels. An antagonist of the ectonucleotidase CD39 reversed 1,25(OH)2D3-mediated inhibition of the IL-17A response. CONCLUSION: Patients with severe asthma exhibit increased levels of TH17 cytokines, which are not inhibited by steroids. 1,25(OH)2D3 inhibits TH17 cytokine production in all patients studied, irrespective of their clinical responsiveness to steroids, identifying novel steroid-enhancing properties of vitamin D in asthmatic patients.

Long-Term Effectiveness of Anti-IL-4R Therapy Following Suboptimal Response to Anti-IL-5/5R Therapy in Severe Eosinophilic Asthma.

BACKGROUND: Dupilumab is an anti-IL-4R monoclonal antibody (mAb) with proven efficacy in severe eosinophilic asthma (SEA). A suboptimal response to anti-IL-5/5R mAbs is seen in some patients with ongoing evidence of type 2 (T2) inflammation. OBJECTIVE: To understand whether targeting IL-13 pathways with dupilumab in these patients may lead to better clinical outcomes. METHODS: We performed a retrospective analysis of the extended clinical effectiveness of dupilumab up to 2 years of treatment in patients with SEA who had not responded adequately to anti-IL-5/5R biologics. The ability to achieve clinical remission and the change in the remission domains of exacerbation rate (AER), maintenance oral corticosteroid dose (mOCS), lung function (forced expiratory volume in 1 second), and asthma control (Asthma Control Questionnaire 6) were recorded. RESULTS: Thirty-seven patients (mean age 41 years, 70% female) were included in the analysis. The mean (standard deviation) AER fell by almost 90% from 3.16 (1.28) at dupilumab initiation to 0.35 (0.72) after 1 year. The median (interquartile range) mOCS dose (n = 20) fell from 10 (5-25) mg to 0 (0-5) mg at 1 year, with 14 of 20 (70%) able to stop prednisolone altogether. Clinical remission was achieved in 16 of 37 (43%). Patients who achieved remission had a higher pre-IL-5/5R fractional exhaled nitric oxide (FeNO) level (85 [39-198] parts per billion [ppb] vs 75 [42-96] ppb, P = .03). CONCLUSIONS: Significant improvements in clinical outcomes are possible after a switch to dupilumab in patients experiencing a suboptimal response to anti-IL-5/5R therapies. A higher FeNO in poor responders to anti-IL-5/5R who achieve remission with dupilumab is suggestive of an IL-13-driven subphenotype of T2-high asthma in which the eosinophil appears unlikely to play a key role in the disease pathogenesis.

Long-Term Effectiveness of Benralizumab in Eosinophilic Granulomatosis With Polyangiitis.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a multisystemic disease characterized by eosinophilic tissue inflammation. Benralizumab, an anti-IL-5 receptor (anti-IL-5R) monoclonal antibody, induces rapid depletion of eosinophils; its longer-term effect in EGPA is unknown. OBJECTIVE: To assess the real-world effectiveness and clinical remission rates of anti-IL-5R therapy in EGPA. METHODS: We performed a retrospective cohort analysis of patients with EGPA, who commenced treatment with benralizumab. Clinical remission, assessed at 1 year and 2 years after the initiation of benralizumab, was defined as an absence of active vasculitis (Birmingham Vasculitis Activity Score of 0) and an oral corticosteroid (OCS) dose of ≤4 mg/d of prednisolone. "Super-responders" were defined as patients in remission and free of any significant relapses (asthma or extrapulmonary) over the preceding 12 months. The corticosteroid-sparing capacity of benralizumab, patient-reported outcome measures, and characteristics associated with clinical remission and super-responder status were also analyzed. RESULTS: A total of 70 patients completed at least 1 year of treatment with benralizumab, of whom 53 completed 2 years. Of 70 patients, 47 (67.1%) met the definition for clinical remission at 1 year, with a similar proportion in remission at 2 years. Excluding asthma-related relapses, 61 of 70 (87.1%) patients were relapse free at 1 year, and of the 53 who completed 2 years, 45 (84.9%) were relapse free. A total of 67.9% of patients no longer needed any OCS for disease control. No significant difference was seen between antineutrophilic cytoplasmic antibody (ANCA)-positive and ANCA-negative subgroups. CONCLUSIONS: In this real-world setting of patients with EGPA, treatment with benralizumab was well tolerated and resulted in corticosteroid-free clinical remission for the majority of patients.

Use of digital measurement of medication adherence and lung function to guide the management of uncontrolled asthma (INCA Sun): a multicentre, single-blinded, randomised clinical trial.

BACKGROUND: The clinical value of using digital tools to assess adherence and lung function in uncontrolled asthma is not known. We aimed to compare treatment decisions guided by digitally acquired data on adherence, inhaler technique, and peak flow with existing methods. METHODS: A 32-week prospective, multicentre, single-blinded, parallel, randomly controlled trial was done in ten severe asthma clinics across Ireland, Northern Ireland, and England. Participants were 18 years or older, had uncontrolled asthma, asthma control test (ACT) score of 19 or less, despite treatment with high-dose inhaled corticosteroids, and had at least one severe exacerbation in the past year despite high-dose inhaled corticosteroids. Patients were randomly assigned in a 1:1 ratio to the active group or the control group, by means of a computer-generated randomisation sequence of permuted blocks of varying sizes (2, 4, and 6) stratified by fractional exhaled nitric oxide (FeNO) concentration and recruitment site. In the control group, participants were masked to their adherence and errors in inhaler technique data. A statistician masked to study allocation did the statistical analysis. After a 1-week run-in period, both groups attended three nurse-led education visits over 8 weeks (day 7, week 4, and week 8) and three physician-led treatment adjustment visits at weeks 8, 20, and 32. In the active group, treatment adjustments during the physician visits were informed by digital data on inhaler adherence, twice daily digital peak expiratory flow (ePEF), patient-reported asthma control, and exacerbation history. Treatment was adjusted in the control group on the basis of pharmacy refill rates (a measure of adherence), asthma control by ACT questionnaire, and history of exacerbations and visual management of inhaler technique. Both groups used a digitally enabled Inhaler Compliance Assessment (INCA) and PEF. The primary outcomes were asthma medication burden measured as proportion of patients who required a net increase in treatment at the end of 32 weeks and adherence rate measured in the last 12 weeks by area under the curve in the intention-to-treat population. The safety analyses included all patients who consented for the trial. The trial is registered with ClinicalTrials.gov, NCT02307669 and is complete. FINDINGS: Between Oct 25, 2015, and Jan 26, 2020, of 425 patients assessed for eligibility, 220 consented to participate in the study, 213 were randomly assigned (n=108 in the active group; n=105 in the control group) and 200 completed the study (n=102 in the active group; n=98 in the control group). In the intention-to-treat analysis at week 32, 14 (14%) active and 31 (32%) control patients had a net increase in treatment compared with baseline (odds ratio [OR] 0·31 [95% CI 0·15-0·64], p=0·0015) and 11 (11%) active and 21 (21%) controls required add-on biological therapy (0·42 [0·19-0·95], p=0·038) adjusted for study site, age, sex, and baseline FeNO. Three (16%) of 19 active and 11 (44%) of 25 control patients increased their medication from fluticasone propionate 500 µg daily to 1000 µg daily (500 µg twice a day; adjusted OR 0·23 [0·06-0·87], p=0·026). 26 (31%) of 83 active and 13 (18%) of 73 controls reduced their medication from fluticasone propionate 1000 µg once daily to 500 µg once daily (adjusted OR 2·43 [1·13-5·20], p=0·022. Week 20-32 actual mean adherence was 64·9% (SD 23·5) in the active group and 55·5% (26·8) in the control group (between-group difference 11·1% [95% CI 4·4-17·9], p=0·0012). A total of 29 serious adverse events were recorded (16 [55%] in the active group, and 13 [45%] in the control group), 11 of which were confirmed as respiratory. None of the adverse events reported were causally linked to the study intervention, to the use of salmeterol-fluticasone inhalers, or the use of the digital PEF or INCA. INTERPRETATION: Evidence-based care informed by digital data led to a modest improvement in medication adherence and a significantly lower treatment burden. FUNDING: Health Research Board of Ireland, Medical Research Council, INTEREG Europe, and an investigator-initiated project grant from GlaxoSmithKline.

Eosinophilic granulomatosis with polyangiitis: case report and literature review.

Eosinophilic granulomatosis with polyangiitis (EGPA), previously known as Churg-Strauss syndrome, is a multisystem disorder characterised by asthma, blood and tissue eosinophilia and small-vessel vasculitis. Eosinophilic tissue infiltration and extravascular granuloma formation can lead to damage in any organ, but it is classically seen to cause pulmonary infiltrates, sino-nasal disease, peripheral neuropathy, renal and cardiac involvement, and rashes. EGPA is part of the anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis syndromes, with the antibody being detected in ∼30-40% of cases and mostly against myeloperoxidase. Two genetically and clinically distinct phenotypes, defined by the presence or absence of ANCA have been identified. Treatment for EGPA focuses on inducing and maintaining disease remission. To date, oral corticosteroids remain first-line agents whilst second-line treatments include immunosuppressants such as cyclophosphamide, azathioprine, methotrexate, rituximab and mycophenolate mofetil. However, long-term steroid usage results in multiple and well-known adverse health effects and new insights into the pathophysiology of EGPA have allowed for the development of targeted biologic therapies, like the anti-eosinophilic, anti-interleukin-5 monoclonal antibodies.

Prescribing Patterns and Treatment Adherence in Patients with Asthma During the COVID-19 Pandemic.

BACKGROUND: The COVID-19 pandemic has witnessed a reduction in asthma exacerbations across the United Kingdom. Several factors may underpin this, including reduced transmission of seasonal viruses and improved adherence to inhaled corticosteroids (ICS). However, little is known about how ICS use has changed during the pandemic. OBJECTIVE: To identify prescribing patterns for asthmatics during the pandemic. METHODS: Using the OpenPrescribing database, we retrospectively analyzed prescribing patterns of ICS, salbutamol and peak flow meters from January 2019 to January 2021 across England. In addition, using a sample asthma cohort at 3 primary care practices in London, we assessed individual prescription patterns. RESULTS: A sharp increase in national ICS prescriptions occurred in March 2020 representing a 49.9% increase compared with February 2020. The sample cohort included 1132 patients (762 ICS treated across both years). Overall ICS adherence improved in 2020 (P < .001), with the proportion of patients meeting "good adherence" (≥75%) increasing from 33.9% to 42.0% (P < .001). The March 2020 spike predominantly reflected improved adherence rather than a hoarding effect of multiple inhalers. Female gender and increasing age were associated with the most significant improvements in adherence. A similar spike in salbutamol occurred in March 2020; however, an overall reduction in salbutamol prescriptions occurred in 2020 (P = .039). National figures highlighted a progressive increase in prescription of peak flow meters over 2020. CONCLUSION: ICS adherence rates remain low; however, a modest improvement in adherence was observed during the first year of the COVID-19 pandemic. Salbutamol prescription rates reduced over the same time period, whereas prescriptions for peak flow meters have steadily increased.

Transitioning Asthma Care From Adolescents to Adults: Severe Asthma Series.

Children with asthma grow to become adults with asthma. Adolescents are not simply older children and do not automatically transform into independent adults, nor do they become proficient in self-management of their condition overnight. Adolescence is a high-risk time for many people with asthma, with increased risk of asthma-related morbidity and mortality. Children with high-risk asthma attend hospital-based asthma clinics with their parents until they reach young adulthood, and parents usually take on the significant burden of disease management on behalf of their children. Once patients are transferred to adult medical teams, many will continue to have limited knowledge about their asthma, limited understanding of how to manage their symptoms and comorbidities, and limited comprehension of how and why to take their regular medication. Adolescence is a critical time of change during which young people yearn for autonomy. Effective transition gives young people the skills and knowledge necessary to manage their health independently and provides the substrate for autonomous care, the bed rock of long-term conditions. This review focuses on the challenges of adolescent health care and provides guidance on how to take a planned, patient-centered approach to ensure each transition is effective and safe.

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.

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.