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.

Cost saving of switching to equivalent inhalers and its effect on health outcomes.

BACKGROUND: Switching inhalers to cheaper equivalent products is often advocated as a necessary cost saving measure, yet the impact on patient's health and healthcare utilisation has not been measured. METHODS: We identified asthma and chronic obstructive pulmonary disease (COPD) patients from UK primary care electronic healthcare records between 2000 and 2016. A self-controlled case series was used to estimate incidence rate ratios (IRR); comparing outcome rates during the risk period, 3 months after the exposure (financially motivated switch), and control periods (preswitch and postrisk period). Four outcomes were assessed: disease exacerbation, general practitioner consultation, non-specific respiratory events and adverse-medication events. Medication possession ratio (MPR) was calculated to assess adherence. 2017 National Health Service indicative prices were used to estimate cost differences per equivalent dose. RESULTS: We identified a cohort of 569 901 asthma and 171 231 COPD regular inhaler users, 2% and 6% had been switched, respectively. Inhaler switches between a brand-to-generic inhaler, and all other switches (brand-to-brand, generic-to-generic, generic-to-brand), were associated with reduced exacerbations (brand-to-generic: IRR=0.75, 95% CI 0.64 to 0.88; all other: IRR=0.79, 95% CI 0.71 to 0.88). Gender, age, therapeutic class, inhaler device and inhaler-technique checks did not significantly modify this association (p<0.05). The rate of consultations, respiratory-events and adverse-medication events did not change significantly (consultations: IRR=1.00, 95% CI 0.99 to 1.01; respiratory-events: IRR=0.96, 95% CI 0.95 to 0.97; adverse-medication-events: IRR=1.05, 95% CI 0.96 to 1.15). Adherence significantly increased post-switch (median MPR: pre-switch=54%, post-switch=62%; p<0.001). Switching patients, in the cohort of regular inhaler users, to the cheapest equivalent inhaler, could have saved around £6 million annually. CONCLUSION: Switching to an equivalent inhaler in patients with asthma or COPD appeared safe and did not negatively affect patient's health or healthcare utilisation.

Ethical, philosophical, and practical considerations in adherence to therapy in sleep medicine.

PURPOSE OF REVIEW: We consider a series of linked philosophical issues created by non-adherence to therapy in sleep medicine. RECENT FINDINGS: First, the difficulty of measuring rates of adherence creates an epistemic problem regarding the efficacy of prescribed treatments. Secondly, as diseases are often classified as refractory based on apparent failure of standard medicines, the validity of this classification faces a similar epistemic crisis. This in turn produces ethical issues when therapies are restricted to cases deemed refractory. It also calls into question, if the patient does not take the medicines as prescribed, what they do with them; and the prospect of potential drug diversion arises. Education of patients seems to be of limited help in addressing these issues; what may be needed is a revision of the patient-prescriber relationship to move away from blame when nonadherence occurs. We close by revisiting an ancient debate in the philosophy of action, which may shed light on what such a revised relationship would require. SUMMARY: More honest and trusting patient-physician relationships, and a much more accurate sense of when nonadherence is occurring and why, may result from a better practical and philosophical understanding of the patient's decision-making.

Effectiveness and side-effect profile of stimulant therapy as monotherapy and in combination in the central hypersomnias in clinical practice.

Effectiveness and side-effect profile data on pharmacotherapy for daytime sleepiness in central hypersomnias are based largely upon randomized controlled trials. Evidence regarding the use of combination therapy is scant. The aim of this study was to examine the effectiveness and occurrence of drug-related side effects of these drugs in routine clinical practice. Adult patients diagnosed with a central hypersomnia during a 54-month period at a tertiary sleep disorders centre were identified retrospectively. Side effects were recorded at every follow-up visit. A total of 126 patients, with 3275 patient-months of drug exposure, were categorized into narcolepsy type 1 (n = 70), narcolepsy type 2 (n = 47) and idiopathic hypersomnia (n = 9). Modafinil was the most common drug used as a first-line treatment (93%) and in combination therapy (70%). Thirty-nine per cent of the patients demonstrated a complete, 25% partial and 36% a poor response to treatment. Combination treatment improved daytime sleepiness in 55% of the patients with residual symptoms despite monotherapy. Sixty per cent of patients reported side effects, and 30% reported treatment-limiting side effects. Drugs had similar side-effect incidence (P = 0.363) and their side-effect profile met those reported in the literature. Twenty-seven per cent of the patients received combination treatment and had fewer side effects compared to monotherapy (29.4% versus 60%, respectively, P = 0.001). Monotherapy appears to achieve satisfactory symptom control in most patients with central hypersomnia, but significant side effects are common. Combination therapy appears to be a useful and safe option in patients with refractory symptoms.

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.

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.

A Systematic Review of Patient-Reported Adherence Measures in Asthma: Which Questionnaire Is Most Useful in Clinical Practice?

BACKGROUND: Suboptimal adherence to inhaled corticosteroid in asthma is a worryingly prevalent yet modifiable factor in uncontrolled disease. Several objective measures of adherence exist, but they are time-consuming. The use of patient-reported adherence measures (PRAMs) could therefore offer a time-efficient pragmatic approach to assessing adherence in clinical practice and potentially the appropriate interventions to improve it. OBJECTIVES: To identify the PRAMs available for asthma and assess their psychometric quality, accessibility, and usefulness in clinical practice, as well as to provide recommendations for clinicians based on these findings. METHODS: We conducted a systematic review of six databases. Articles included in this study were English language, full-text, original, asthma-specific PRAMs or development/validation studies of a generic PRAM that had been administered to adults with asthma, investigated inhaled corticosteroid adherence in adults (aged 18 years and older), and assessed at least one COnsensus-based Standards for the selection of health Measurement INstruments measurement property. RESULTS: We included 15 PRAM developmental and/or validation studies in this systematic review. Studies evaluated a range of COnsensus-based Standards for the selection of health Measurement INstruments measurement properties, but none evaluated all of them. CONCLUSIONS: Based on this review, we recommend that when a PRAM is used, it should be the Test of the Adherence to Inhalers. However, the Adherence Starts with Knowledge-20 and Adherence Starts with Knowledge-12 may also be useful. Our results highlight the need for PRAM developers to assess questionnaires robustly and provide guidance for clinicians regarding how to act on PRAM answers by developing materials such as decision support tool kits.

The role of the clinical pharmacist in the respiratory or sleep multidisciplinary team.

The role of the pharmacist has evolved significantly, not least over the last 20 years. It delivers a skilled profession with a vital role in medicines optimisation and the management of patients with a respiratory or sleep disorder. While pharmacists are capable of acting as independent practitioners delivering direct patient care, this article explores their contribution to multidisciplinary teams within asthma, COPD, cystic fibrosis, tuberculosis, interstitial lung disease and sleep medicine. Having identified patient cohorts needing specialist medicines support, notably those with poor medicines adherence or specific medicines-related needs (for example during adolescence, or women who are pregnant or breastfeeding), these pharmacists work within primary, secondary and specialist tertiary care. The aim of this review is to share and inspire innovative models of working to include more pharmacists in respiratory and sleep medicine.

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.

Improving adherence in chronic airways disease: are we doing it wrongly?

Non-adherence to medicines is a significant clinical and financial burden, but successful strategies to improve it, and thus bring about significant improvements in clinical outcome, remain elusive. Many barriers exist, including a lack of awareness amongst some healthcare professionals as to the extent and impact of non-adherence and a dearth of skills to address it successfully. Patients may not appreciate that they are non-adherent, feel they cannot disclose it or underestimate its impact on their health in the short and longer term. In describing the evidence-based frameworks that identify the causal factors behind medicines taking (or not taking) behaviours, we can start to personalise interventions to enable individuals to make informed decisions about their treatments and thus overcome real and perceived barriers to adherence. EDUCATIONAL AIMS: To understand the underlying principles of why a patient may or may not take medicines as agreed.To choose targeted interventions to support better adherence.

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 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.

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.