Long-term Oral Corticosteroid Research Articles

Management of Fracture Risk in Patients with Chronic Obstructive Pulmonary Disease (COPD): Building a UK Consensus Through Healthcare Professional and Patient Engagement.

IntroductionOsteoporosis and bone fractures are common in chronic obstructive pulmonary disease (COPD) and contribute significantly to morbidity and mortality. Current national guidance on COPD management recommends addressing bone health in patients, however, does not detail how. This consensus outlines key elements of a structured approach to managing bone health and fracture risk in patients with COPD.MethodsA systematic approach incorporating multifaceted methodologies included detailed patient and healthcare professional (HCP) surveys followed by a roundtable meeting to reach a consensus on what a pathway would look like.ResultsThe surveys revealed that fracture risk was not always assessed despite being recognised as an important aspect of COPD management by HCPs. The majority of the patients also stated they would be receptive to discussing treatment options if found to be at risk of osteoporotic fractures. Limited time and resource allocation were identified as barriers to addressing bone health during consultations. The consensus from the roundtable meeting was that a proactive systematic approach to assessing bone health should be adopted. This should involve using fracture risk assessment tools to identify individuals at risk, investigating secondary causes of osteoporosis if a diagnosis is made and reinforcing non-pharmacological and preventative measures such as smoking cessation, keeping active and pharmacological management of osteoporosis and medicines management of corticosteroid use. Practically, prioritising patients with important additional risk factors, such as previous fragility fractures, older age and long-term oral corticosteroid use for an assessment, was felt required.ConclusionThere is a need for integrating fracture risk assessment into the COPD pathway. Developing a systematic and holistic approach to addressing bone health is key to achieving this. In tandem, opportunities to disseminate the information and educational resources are also required.

PRS10 COST-UTILITY ANALYSIS OF MEPOLIZUMAB VERSUS BENRALIZUMAB FOR SEVERE EOSINOPHILIC ASTHMA IN THE COLOMBIAN HEALTHCARE SYSTEM

BACKGROUND: Adding mepolizumab to standard treatment with inhaled corticosteroids and controller medications decreases asthma exacerbations and long-term oral corticosteroid use in patients with severe eosinophilic asthma. However, since new biological therapies are available in the Colombian healthcare system, it is necessary to establish their cost-effectiveness to inform local payers and decision-makers. To evaluate the cost-effectiveness of new biologics, mepolizumab and benralizumab, to treat adults with severe eosinophilic asthma in Colombia. A Markovian model was used to determine the incremental cost per quality-adjusted life year (QALY) of mepolizumab plus standard of care (SoC) versus benralizumab plus SoC from the payer’s perspective. In a monthly cycle, patients could transition between five health states (three asthma treatment states, asthma related death, and all-cause mortality) and three types of exacerbation events (exacerbations requiring either OCS burst, emergency department visit or hospitalization). Lifetime horizon was used. A network metanalysis (Busse 2019) was used for efficacy data, and local life tables for death probabilities. Costs were estimated following the methods recommended by the local health technology assessment agency. Costs and benefits were discounted at 5% and expressed in 2018 USD (1 USD = 2,956 COP). At the end of the simulation, mean cost of prevention of exacerbations and long-term oral steroid were $69.22 less per patient in mepolizumab, and mean therapy cost was $6,990.0 less per patient in mepolizumab. Treatment with mepolizumab plus SoC and benralizumab plus SoC resulted in 8.97 and 8.73 QALYs respectively. Findings were consistent in the probabilistic sensitivity analysis. Mepolizumab is a dominating alternative compared with benralizumab in the treatment of adults with severe eosinophilic asthma in Colombia from the payer’s perspective. Funding: GSK (PRJ2813).

A056 Managing and Monitoring Long-term Oral Corticosteroids – How Good Are We and Do We Follow Best Practice Guidelines?

Background: Long-term (defined as >1 month) oral corticosteroids are widely used for chronic inflammatory and autoimmune conditions. In cardiology, the primary indications are transplantation, cardiac sarcoidosis and large vessel vasculitis. Minimising organ-based complications including infection (Pneumocystis jiroveci pneumonia (PJP)), gastro-intestinal (GI) bleeding and osteoporosis warrant consideration but guidelines vary between specialties and co-existing treatments. The aim of this study was to assess prescribing patterns between specialties at Auckland, Waitemata and Counties Manukau District Health Boards. Method: An anonymised survey of cardiologists, respiratory, oncology, haematology, endocrinology, infectious diseases and rheumatologists with questions regarding prescribing and monitoring practices for: i) PJP prophylaxis, ii) proton pump inhibitor (PPI) for GI protection, iii) baseline bone mineral density (BMD) and iv) bisphosphonate use. Results: In total 44 responders; cardiology n=16 vs. other n=28. PJP prophylaxis was prescribed n= 5 (31%) of cardiologists compared to n=23 (96%) of other specialties. Cardiologists were less likely to prescribe bisphosphonates n=1 (6%) than other specialists n=10 (36%, p value = 0.01) but with similar prescription of PPI and baseline BMD (Figure 1). Conclusion: Prescription of PJP prophylaxis, bisphosphonates and PPIs are lower amongst cardiologists. PPI and bisphosphonates use were high particularly amongst non-cardiologists increasing the patient pill burden but may be unnecessary in the absence of previous GI complications or co-existing NSAID use and moderate-high risk of fracture on BMD. Consensus guidelines for cardiologists aimed at standardising pre-treatment assessment and prevention of prove patient care and prevent unnecessary therapy. [Formula presented]

Prevalence of oral corticosteroid use in the German severe asthma population.

AimsWe investigated the prevalence of severe asthma, its comorbidities, and especially the use of oral corticosteroid (OCS) therapy in patients with severe asthma.MethodsPooled data from 3 961 429 patients insured (with statutory health insurance) during the year 2015 were analysed. Prevalence rates of severe asthma and its OCS-associated comorbidities in patients on high-dosage (HD) inhaled corticosteroid (ICS) in combination with a long-acting β agonist (LABA) therapy were compared with those of patients who were also treated with OCSs.ResultsThe asthma prevalence was 7.3%, of which 8.7% (0.6% absolute) were treated with HD-ICS/LABAs. Of these, 33.6% received additional OCSs with calculated dosages between 0.9 and 9.1 mg·day−1. More than 80% of patients on HD-ICS/LABAs had at least one comorbidity. Disorders of the heart (67.5%), metabolism/ nutrition (51.4%), psychiatric disorders (36.0%), skeletal muscle/connective tissue and bone disorders (20.3%), and eye disorders (20.0%) were predominant. The prevalence of these disorders increased for patients also receiving OCS therapy, depending on the length of treatment. Mean therapy costs ranged from €4266 per patient without OCS therapy to €11 253 per patient on long-term OCS treatment. The largest share of costs was attributable to inpatient care.ConclusionThe analyses show that OCSs are frequently prescribed in patients receiving HD-ICS/LABAs because of severe asthma and are they are frequently associated with adverse effects commonly reported with steroid usage. These data support a necessary change in severe asthma treatment, which is reflected in current treatment guidelines.

Oral Corticosteroid Use for the Treatment of Chronic Eosinophilic Disease: A Patient's and His Physician's Experience.

This article, coauthored by a patient with eosinophilic granulomatosis with polyangiitis (EGPA) initially presenting as severe eosinophilic asthma and his physician-specialist, discusses the use and management of oral corticosteroid (OCS) treatment. It also considers the importance of early diagnosis of a rare disease and patient education. The patient describes his journey from progressive worsening of asthma and eventual diagnosis of EGPA to long-term OCS treatment and then participation in a clinical trial for this rare disease, involving the introduction of targeted biologic therapy with OCS tapering. The physician describes the importance of patient referral to obtain a correct diagnosis and optimal maintenance treatment, the balance between risk of adverse events associated with long-term OCS use and benefits of disease control, and various aspects of patient participation in clinical trials. Finally, the patient describes the role of continual patient education in the management of disease and OCS treatment. These considerations can apply to all chronic inflammatory diseases requiring maintenance OCS treatment.Funding: AstraZeneca.

Time Trade-off Utility Values in Noninfectious Uveitis

To investigate time trade-off (TTO) utility values in patients with noninfectious uveitis and determine whether patient demographics and clinical characteristics are associated with utility scores. Time trade-off utility analysis. Setting: A tertiary care uveitis center in San Francisco, California, USA. One hundred and four consecutive adults with noninfectious uveitis, enrolled between November 2016 and February 2017. TTO utility values, as collected by an interviewer-guided survey. Information regarding general health, ocular symptoms, and religion was also collected and medical record review was conducted to record anatomic location of uveitis, disease activity, visual acuity, and treatments. Multivariable regression analysis with backward selection was used to identify variables associated with TTO values. Median TTO score was 0.975 (interquartile range [IQR]: 0.8-1.0), corresponding to trading a median 1.28 years of remaining life for healthy eyes (IQR: 0-6.29). Regression analysis revealed that worse eye visual acuity, >6months of oral corticosteroid use, and current antidepressant use were associated with lower TTO scores (P= .008, P= .006, P= .008, respectively), controlling for age and sex. In particular, patients who had been taking oral corticosteroids for more than 6months, regardless of dose, were 10.5 times more likely to trade 20% or more years of remaining life (TTO ≤0.8) than patients not taking oral corticosteroids (95% confidence interval: 2.3, 48.1; P= .002). Patients with noninfectious uveitis had measurable, though modest, reductions in quality of life, as assessed by TTO, and these decreases were significantly associated with visual acuity in the worse eye and long-term oral corticosteroid use.

Crusted scabies in patients with long-term use of oral corticosteroid with different underlying diseases – case series

People with a weakened immune system may develop the severe form of scabies called crusted scabies. We have two cases of female patients with history of using long-term oral corticosteroid and then developing scabies infection. The first patient had other comorbidities which caused her become more susceptible while the second patient had been diagnosed with bullous pemphigoid. Both patients complained thick crust on some parts of their bodies, accompanied with itchy papules. Based on microscopic examination from lesion scraping, we found the adult form of sarcoptes scabiei and crusted scabies diagnosis was established. The lesions were improving when they got combination of topical sulfur precipitate, salicylic acid, and permethrine 5%. Crusted scabies is characterized by hyperkeratosis and crusting of the skin due to the profuse proliferation of mites resulting from an altered host response. Combination of topical antiscabies and keratolytic can make the crusts thinner and improve topical absorption.

Future Risks in Patients With Severe Asthma.

A major burden of severe asthma is the future risk of adverse health outcomes. Patients with severe asthma are prone to serious exacerbation and deterioration of lung function and may experience side effects of medications such as oral corticosteroids (OCSs). However, such future risk is not easily measurable in daily clinical practice. In particular, currently available tools to measure asthma control and asthma-related quality of life incompletely predict the future risk of medication-related morbidity. This is a significant issue in asthma management. This review summarizes the current evidence of future risk in patients with severe asthma. As future risk is poorly perceived by controlled asthmatics, our review focuses on the risk in patients with ‘controlled’ severe asthma. Of note, it is likely that long-term OCS therapy may not prevent future asthma progression, including lung function decline. In addition, the risk of drug side effects increases even during low-dose OCS therapy. Thus, novel treatments are highly desirable for reducing future risks without any loss of asthma control.

Consequences of long-term oral corticosteroid therapy and its side-effects in severe asthma in adults: a focused review of the impact data in the literature.

This review provides an overview of the role of long-term treatment of severe asthma with oral corticosteroids (OCS) and its associated side-effects in adults. It is based on a systematic literature search conducted in MEDLINE, Embase and the Cochrane Library to identify relevant studies. After a short overview of severe asthma and its treatment we present studies showing a dose-response relationship in asthmatic patients treated with OCS and then consider by organ systems the undesired effects demonstrated in clinical and epidemiological studies in patients with OCS-dependent asthma. It was found that the risk of developing various OCS-related complications, including infections, diabetes and osteoporosis as well as psychiatric disorders, was higher for patients with long-term exposure to OCS compared with control groups. In addition, studies showed a significant increase in healthcare resource utilisation due to OCS treatment. Therefore, it is incumbent on every clinician to carefully weigh the potential benefit of preventing loss of asthma control against this risk before opting to prescribe long-term OCS therapy. Effective corticosteroid-sparing strategies must be used and should aim at short-term use with the lowest effective dose and start tapering as soon as possible until OCS therapy is terminated.

Healthcare resource utilization and costs associated with long-term corticosteroid exposure in patients with systemic lupus erythematosus

Objective To evaluate the association between exposure to oral corticosteroids and future healthcare resource utilization and costs for patients with systemic lupus erythematosus. Methods Adults diagnosed with systemic lupus erythematosus (index date) between 1 January 2008 and 30 June 2013 and naive to oral corticosteroids with continuous health plan enrollment for ≥6 months pre- and ≥5 years post-index were identified from a large health plan claims database. Per-patient monthly average daily dose of oral corticosteroids (prednisone or its equivalent) was calculated for the first 2 years post-index to categorize patients into four steroid exposure cohorts: low (≤5 mg/day), medium (6-20 mg/day), high (>20 mg/day) and no steroids. Differences in healthcare resource utilization and total healthcare costs during the third year post-index across corticosteroid exposure cohorts were modeled with adjustment for baseline characteristics. Results The study included 18,618 systemic lupus erythematosus patients (163 high dose, 1127 medium dose, 6717 low dose and 10,611 no steroids). Compared to low-dose corticosteroid users, high-dose corticosteroid users were more likely to have emergency room visits (39.3% vs. 29.7%; p = 0.0085) and to be hospitalized (21.5% vs. 12.3%; p = 0.0005). After adjustment for baseline characteristics, they also had significantly greater average annual total healthcare costs (US$60,366 vs. US$18,777; p < 0.0001). A 1 mg increase in corticosteroid average daily dose was associated with 1.07 times the average annual costs after adjusting for baseline characteristics ( p < 0.0001). Conclusion Long-term high-dose oral corticosteroid use was associated with significantly greater future healthcare resource utilization and costs. Judicious reduction in daily steroid dose may decrease the imminent economic burden associated with high-dose steroid use in systemic lupus erythematosus.

Long-Term Oral Corticosteroid Use and Related Infections in Elderly Patients with Severe Asthma

Long-Term Oral Corticosteroid Use and Related Infections in Elderly Patients with Severe Asthma

Evaluation of Potential Continuation Rules for Mepolizumab Treatment of Severe Eosinophilic Asthma

Mepolizumab significantly reduces exacerbations in patients with severe eosinophilic asthma. The early identification of patients likely to receive long-term benefit from treatment could ensure effective resource allocation. To assess potential continuation rules for mepolizumab in addition to initiation criteria defined as 2 or more exacerbations in the previous year and blood eosinophil counts of 150 cells/μL or more at initiation or 300 cells/μL or more in the previous year. This post hoc analysis included data from 2 randomized, double-blind, placebo-controlled studies (NCT01000506 and NCT01691521) of mepolizumab in patients with severe eosinophilic asthma (N= 1,192). Rules based on blood eosinophils, physician-rated response to treatment, FEV1, Asthma Control Questionnaire (ACQ-5) score, and exacerbation reduction were assessed at week 16. To assess these rules, 2 key metrics accounting for the effects observed in the placebo arm were developed. Patients not meeting continuation rules based on physician-rated response, FEV1, and the ACQ-5 score still derived long-term benefit from mepolizumab. Nearly all patients failing to reduce blood eosinophils had counts of 150 cells/μL or less at baseline. For exacerbations, assessment after 16 weeks was potentially premature for predicting future exacerbations. There was no evidence of a reliable physician-rated response, ACQ-5 score, or lung function-based continuation rule. The added value of changes in blood eosinophils at week 16 over baseline was marginal. Initiation criteria for mepolizumab treatment provide the best method for assessing patient benefit from mepolizumab treatment, and treatment continuation should be reviewed on the basis of a predefined reduction in long-term exacerbation frequency and/or oral corticosteroid dose.

Monitoring long-term oral corticosteroids.

Corticosteroids are synthetic analogues of human hormones normally produced by the adrenal cortex. They have both glucocorticoid and mineralocorticoid properties. The glucocortoid components are anti-inflammatory, immunosuppressive, anti-proliferative and vasoconstrictive. They influence the metabolism of carbohydrate and protein, in addition to playing a key role in the body’s stress response. Mineralocorticoid’s main significance is in the balance of salt and water concentrations. Due to the combination of these effects, corticosteroids can cause many adverse effects. Oral corticosteroids are absorbed systemically and are therefore more likely to cause adverse effects than topical or inhaled corticosteroids. Furthermore, it is assumed that greater duration of treatment will lead to a greater number of adverse effects, and therefore the most at risk group are those taking high dose, long-term oral corticosteroids (LTOC). High dose is defined as a prescription of >5 mg oral prednisolone and long term as duration of treatment >1 month (based on National Institute for Health and Care Excellence guidance for patient’s ’at risk' of systemic side effects). Parameters to be monitored in primary care include weight, blood pressure, triglycerides, glucose and urea and electrolytes. From clinical experience within the general practice setting, the authors propose that these patients do not receive adequate baseline monitoring before starting corticosteroids nor are these markers monitored consistently thereafter. This project intended to evidence this claim, evaluate the adverse effect profile and improve monitoring in this patient group. The initial audit of 22 patients, within a single general practice, detected at least one documented adverse effect in 64% of patients, while 41% reported more than one adverse effect. 45% had recorded weight gain, 18% had recorded osteoporosis, 18% had at least one recorded cataract, 14% had recorded Hypertension, 14% had recorded diabetes mellitus, 9% had recorded dyspepsia and 5% had a recorded psychiatric complaint. All of these recorded conditions were either directly attributed to steroid medication or occurred since LTOC were prescribed. The aim of this project was to increase the percentage of patients on LTOC with complete baseline monitoring to 100%. ’Baseline monitoring' was defined as a measurement taken within the previous 5 years. Although somewhat arbitrary, 5 years was felt to be the maximum timeframe in which monitoring would still be relevant for comparison following introduction of LTOC. Quality improvement methodology was used throughout this project with multiple PDSA (Plan, Study, Do and Act) cycles. Through this, a monitoring system and protocol for patients taking LTOC was developed. As a result of this project, five adverse effects were detected in five different patients. These included two cases of secondary hypertension, one case of diabetes mellitus, one cataract and one case of adrenal insufficiency. 12 out of 20 patients achieved complete baseline monitoring. While this study did not fully achieve its aim, the aim was deliberately ambitious. As not all patients in this study attended for monitoring, a figure of 100% was impossible to achieve. The remaining ’incompletely monitored patients' had some but not all parameters measured. The creation of a staff protocol and increased clinical experience will ensure that complete monitoring takes place in the future. In conclusion, this project has shown that adverse effects from LTOC are prevalent in a single general practice population. It is also shown that monitoring for LTOC adverse effects is inadequate but can be improved relatively easily as skills and competencies from other medication monitoring systems already exist within healthcare settings and are immediately transferable.

From dizziness to severe ataxia and dysarthria: New cases of anti-Ca/ARHGAP26 autoantibody-associated cerebellar ataxia suggest a broad clinical spectrum

In 2010, a novel anti-neuronal autoantibody, termed anti-Ca, was described in a patient with subacute cerebellar ataxia, and Rho GTPase-activating protein 26 (ARHGAP26) was identified as the target antigen. Recently, three additional cases of anti-Ca-positive cerebellar ataxia have been published. In addition to ataxia, cognitive decline and depression have been observed in some patients. Here, we report two new cases of anti-Ca-associated autoimmune cerebellar ataxia.Patient 1 presented with dizziness and acute yet mild limb and gait ataxia. Symptoms stabilized with long-term oral corticosteroid therapy but transiently worsened when steroids were tapered. Interestingly, both initial occurrence and worsening of the patient's neurological symptoms after steroid withdrawal were accompanied by spontaneous cutaneous hematomas. Patient 2 initially presented with an increased startle response and myoclonic jerks, and subsequently developed severe limb and gait ataxia, dysarthria, oculomotor disturbances, head and voice tremor, dysphagia, cognitive symptoms and depression. Steroid treatment was started five years after disease onset. The symptoms then responded only poorly to corticosteroids. At most recent follow-up, 19 years after disease onset, the patient was wheelchair-bound.These cases extend the clinical spectrum associated with anti-ARHGAP26 autoimmunity and suggest that early treatment may be important in patients with this rare syndrome.

Safety issues related to the use of prescription drugs in patients with chronic diseases: a bibliographic review

A literature review was conducted with the aim of investigating the impact of treatments associated with an increased risk of hypertension, hyperglycaemia, hyperkalaemia, bone fracture and serotonin syndrome, by taking into account the most prevalent pathologies, the drugs most frequently prescribed at the outpatient level, as well as the adverse effects they produce. A bibliographical search of scientific publications in MEDLINE, published between 1 January 2006 and 31 December 2015 in English and Spanish, was conducted using 21 keywords. Data, primarily from editorials, non-US government supported research, and reviews, were collected. Other data sources included the websites for the Spanish Agency of Medicines and Medical Devices and the European Medicines Agency, information bulletins on therapeutic information (e.g. the International Society of Drug Bulletins), other guidelines and reference books. From the 24,083 publications identified, 33 articles were selected and their full texts retrieved; 41 articles were included from the references from these articles. Other sources of data were 16 documents from regulatory agencies, seven bulletins, nine guidelines and two books. Approximately 25 therapeutic groups, including nonsteroidal anti-inflammatory drugs, β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, opioid analgesics, certain antidiabetics, antipsychotics, benzodiazepines and long-term oral corticosteroids, were found to be the most frequently involved in medication-related problems. This review has helped identify a set of drugs that should be included in a strategy for ‘high-alert medications’ and in ambulatory care medication revisions for preventing adverse drug reactions, especially the therapeutic groups included in the high-risk drugs list for chronic or geriatric patients and those drugs responsible for emergency visits and hospital admissions.

Potentially (near) fatal asthma.

Potentially (near) fatal asthma (PFA) defines a subset of patients with asthma who are at increased risk for death from their disease. The diagnosis of PFA should motivate treating physicians, health professionals, and patients to be more aggressive in the monitoring, treatment, and control of this high-risk type of asthma. A diagnosis of PFA is made when any one of the following are present: (1) a history of endotracheal intubation from asthma, (2) acute respiratory acidosis (pH < 7.35) or respiratory failure from acute severe asthma, (3) two or more episodes of acute pneumothorax or pneumomediastinum from asthma, (4) two or more episodes of acute severe asthma, despite the use of long-term oral corticosteroids and other antiasthma medications. There are two predominant phenotypes of near-fatal exacerbations: "subacute" exacerbation and "hyperacute" exacerbation. The best way to "treat" acute severe asthma is 3-7 days before it occurs (i.e., at the onset of symptoms or change in respiratory function) and to optimize control of asthma by decreasing the number of symptomatic days and the days and/or nights that require rescue therapy and increasing baseline respiratory status in "poor perceivers." PFA is treated with a multifaceted approach; physicians and health-care professionals should appreciate limitations of pharmacotherapy, including combination inhaled corticosteroid-long-acting β-agonist products as well as addressing nonadherence, psychiatric, and socioeconomic issues that complicate care.

Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial

Interleukin 13 is a central mediator of asthma. Tralokinumab is a human interleukin-13 neutralising monoclonal antibody. We aimed to assess the efficacy and safety of two dosing regimens of tralokinumab in patients with severe uncontrolled asthma. We did a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 2b study at 98 sites in North America, South America, Europe, and Asia. Patients aged 18-75 years with severe asthma and two to six exacerbations in the previous year were randomly assigned (1:1), via an interactive voice-response or web-response system, to one of two dosing regimen groups (every 2 weeks, or every 2 weeks for 12 weeks then every 4 weeks) and further randomised (2:1), via computer-generated permuted-block randomisation (block size of six), to receive tralokinumab 300 mg or placebo for 1 year. All participants received high-dose fluticasone and salmeterol and continued other pre-study controller drugs. Treatment was administered by an unmasked study investigator not involved in the management of patients; all other study site personnel, patients, the study funder, and data analysts were masked to treatment allocation. The primary endpoint was the annual asthma exacerbation rate at week 52 in the intention-to-treat population. Key secondary endpoints included prebronchodilator forced expiratory volume in 1 s (FEV1), Asthma Control Questionnaire-6 (ACQ-6), and Asthma Quality of Life Questionnaire-Standardised Version (AQLQ[S]). This trial is registered with ClinicalTrials.gov, number NCT01402986. Between Oct 4, 2011, and Feb 22, 2014, we randomly assigned 452 patients to receive placebo (n=151) or tralokinumab every 2 weeks (n=150) or every 4 weeks (n=151), of whom 383 (85%) completed the treatment period up to week 52. The annual asthma exacerbation rate at week 52 was similar between patients receiving tralokinumab every 2 weeks (0.91 per patient per year [95% CI 0.76-1.08]) and every 4 weeks (0.97 [0.81-1.14]), and those receiving placebo (0.90 [0.75-1.08]). At week 52, percentage changes in annual asthma exacerbation rate were not significant with tralokinumab every 2 weeks or every 4 weeks versus placebo (6% [95% CI -31 to 33; p=0.709] and -2% [-46 to 29; p=0.904], respectively), with positive changes showing a decrease in exacerbation rate and negative changes showing an increase. Prebronchodilator FEV1 was significantly increased compared with placebo for tralokinumab every 2 weeks (change from baseline 7.3% [95% CI 2.6-12.0]; p=0.003), but not every 4 weeks (1.8% [-2.9 to 6.6]; p=0.448); however, we did not identify significant changes in the other key secondary endpoints. In a post-hoc subgroup analysis of patients not on long-term oral corticosteroids and with baseline FEV1 reversibility of 12% or greater, we noted a non-significant improvement in asthma exacerbation rate (44% [95% CI -22 to 74]; p=0.147) and significant improvements in key secondary endpoints (FEV1 12.2% [1.7-22.7]; p=0.022; ACQ-6 -0.55 [-1.07 to -0.04]; p=0.036; and AQLQ[S] 0.70 [0.12-1.28]; p=0.019) in patients given tralokinumab every 2 weeks (n=33) compared with placebo (n=48). In patients in this subgroup who also had baseline serum dipeptidyl peptidase-4 (DPP-4) higher than the population baseline median, we noted additional improvements in prebronchodilator FEV1, ACQ-6, and AQLQ(S), and, in those with periostin concentrations higher than the median, we noted improvements in asthma exacerbation rate, prebronchodilator FEV1, and ACQ-6. The incidence of treatment-emergent adverse events was similar between the tralokinumab and placebo groups. Treatment-emergent serious adverse events regarded as related to the study drug were pneumonia (one [1%] patient in the placebo group), pneumococcal pneumonia (one [1%] in the tralokinumab every 2 weeks group), angioedema (one [1%] in the placebo group), and worsening asthma (one [1%] in the tralokinumab every 2 weeks group and two [1%] in the tralokinumab every 4 weeks group). In this phase 2b study, both tralokinumab regimens had an acceptable safety and tolerability profile but did not significantly reduce asthma exacerbation rates in patients with severe uncontrolled asthma. Improvement in FEV1 with tralokinumab given every 2 weeks and results of post-hoc subgroup analyses suggested a possible treatment effect in a defined population of patients with severe uncontrolled asthma. This effect is being further investigated in ongoing phase 3 trials, along with the potential utility of DPP-4 and periostin as biomarkers of interleukin-13 pathway activation. MedImmune.

Interventions for bronchiectasis: an overview of Cochrane systematic reviews.

Interventions for bronchiectasis: an overview of Cochrane systematic reviews.

Genetic risk factors for decreased bone mineral accretion in children with asthma receiving multiple oral corticosteroid bursts

Long-term intermittent oral corticosteroid (OCS) use in children with asthma leads to significant decreases in bone mineral accretion (BMA). We aimed to identify genetic factors influencing OCS dose effects on BMA in children with asthma. We first performed a gene-by-OCS interaction genome-wide association study (GWAS) of BMA in 489 white participants in the Childhood Asthma Management Program trial who took short-term oral prednisone bursts when they experienced acute asthma exacerbations. We selected the top-ranked 2000 single nucleotide polymorphisms (SNPs) in the GWAS and determined whether these SNPs also had cis-regulatory effects on dexamethasone-induced gene expression in osteoblasts. We identified 2 SNPs (rs9896933 and rs2074439) associated with decreased BMA and related to the tubulin γ pathway. The rs9896933 variant met the criteria for genome-wide significance (P = 3.15 × 10(-8) in the GWAS) and is located on the intron of tubulin folding cofactor D (TBCD) gene. The rs2074439 variant (P = 2.74 × 10(-4) in the GWAS) showed strong cis-regulatory effects on dexamethasone-induced tubulin γ gene expression in osteoblasts (P = 8.64 × 10(-4)). Interestingly, we found that BMA worsened with increasing prednisone dose as the number of mutant alleles of the 2 SNPs increased. We have identified 2 novel tubulin γ pathway SNPs, rs9896933 and rs2074439, showing independent interactive effects with cumulative corticosteroid dose on BMA in children with asthma receiving multiple OCS bursts.

Case of autoantibodies against N‐methyl‐D‐aspartate receptor+/antibodies against myelin‐oligodendrocyte glycoprotein+ multiphasic acute disseminated encephalomyelitis (ADEM)

Case of autoantibodies against N‐methyl‐D‐aspartate receptor+/antibodies against myelin‐oligodendrocyte glycoprotein+ multiphasic acute disseminated encephalomyelitis (<scp>ADEM</scp>)