Corticosteroid Reduction Research Articles

EFFICACY AND SAFETY OF MEPOLIZUMAB IN SEVERE ASTHMA: REAL-LIFE EXPERIENCE IN A TERTIARY CENTER IN SAUDI ARABIA

SESSION TITLE: Obstructive Lung Disease Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Severe asthma is asthma that is uncontrolled despite adherence to maximal optimized controller therapy e.g medium or high dose inhaled steroids with a second controller or maintenance Oral Corticosteroids. Over the past few years, multiple biological therapies have been used to treat severe eosinophilic asthma. One of the first ones approved was Mepolizumab which is an anti-IL-5 antibody that has been utilized to treat severe asthma. Our study aims to evaluate the efficacy and safety of Mepolizumab for the treatment of severe asthma in a real-world severe asthma clinic in a tertiary hospital in Riyadh, Saudi Arabia. METHODS: We did a chart review on severe asthma patients who were started on Mepolizumab in the past two years. Multiple outcomes were observed which include the rate of annual asthma exacerbation, reduction in Oral Corticosteroids (OCS) dose, and improvement in Asthma Control. RESULTS: 53 severe asthma patients ( 75% females ) were on mepolizumab for the past two years. Mepolizumab was switched to Dupilumab in 4 patients. 3 of them were due to lack of effectiveness and one was due to significant headache post-injection. The average age was 45 +/- 13. 69% of patients were early-onset asthmatics (defined as asthma diagnosed < 13 years of age). 63.42% of patients were on Mepolizumab for one year or more. At baseline, patients had an average 18.46 Emergency Room (ER) visits due to asthma exacerbations and 12.8 short courses of Prednisone for asthma attacks. Their average Asthma Control Test (ACT) was 12 +/- 4.7 at baseline. 83% of patients were uncontrolled at baseline. 42% of patients were on daily OCS at baseline. After 12 months, the average ER visits dropped to 1.35 visits (reduction by 92.6%), and the need for short courses of prednisone was reduced to 2.4 courses ( reduction of 81%). At 12 months, 8 patients were off daily steroids (53% of total patients who were of daily steroids at baseline). There was a 36% improvement in ACT score after one year of Mepolizumab (ACT score 17.57) compared to baseline. 42% of patients became controlled after one year of Mepolizumab compared to baseline. CONCLUSIONS: In this retrospective real-life study, we have shown that Mepolizumab had a significant effect in reducing annual asthma exacerbations that require ER visits or short courses of Steroids. It also helped in reducing daily OCS dose. Overall, Mepolizumab was a safe medication as we only had one patient who had one significant side effect that led to its discontinuation. CLINICAL IMPLICATIONS: To the best of our knowledge, this is the first and largest real-life retrospective study in the country that examined the efficacy and safety of Mepolizumab on severe asthma patients. This will help in having better access to this medication and other biological therapies. DISCLOSURES: No relevant relationships by Riyad Al-Lehebi, source=Web Response No relevant relationships by Ali Alqahtani, source=Web Response No relevant relationships by Yahya Asiri, source=Web Response

Significant improvement in lung function and asthma control after benralizumab treatment for severe refractory eosinophilic asthma

Severe eosinophilic asthma is a complex disease and much effort has been made to fully understand its mechanisms. Bronchial remodeling and loss of lung function are important features in asthma, however their key aspects are not completely clear, especially the impact that biological drugs may have on them. One of the key cytokines involved in the pathophysiology of eosinophilic asthma is interleukin-5 (IL-5), which plays a very important role together with other type 2 cytokines and chemokines in the development, transmigration and persistence of eosinophils into airways, such as eotaxin-2 and 3, thymic stromal lymphopoietin (TSLP), IL-33, as well as IL-4 and IL-13. Several monoclonal antibodies have been developed against this cytokine (mepolizumab, reslizumab) or its receptor (benralizumab). Data on the improvement of respiratory function in patients who undergo benralizumab treatment are scarce and partly conflicting. Real-life studies may play a crucial role in clarifying this important aspect.The aim of this retrospective observational real-world study was to evaluate the effect of benralizumab on lung function improvement, exacerbation rate, oral corticosteroids (OCS) reduction and asthma control questionnaire (ACQ) score before and after six months of treatment with benralizumab in a cohort of 20 consecutive patients with severe refractory asthma (SRA) treated at the Pneumology Unit of Local Health Authority, Reggio Emilia, Italy.Add-on therapy with benralizumab allowed to completely suspend OCS in 19 out of 20 patients. Notably, the number of moderate/severe exacerbations dropped significantly (p < 0,0001); as well as an improvement in ACQ score (p < 0,0001). The most relevant data concern respiratory function: the average pre-bronchodilator FEV1 increased by 21.3% (+680 ml) compared to baseline (p = 0,0006). Moreover, the improvement in morning PEF (+66,6 l/min) confirmed the benefit of benralizumab (p = 0,02). The improvement in respiratory function was significantly higher in patients with blood eosinophilia greater than 500 cells/μL and chronic rhinosinusitis with nasal polyps (CRSwNP).This study underlies a noticeable improvement in respiratory function, much higher than what has been observed in literature so far. This aspect, together with the others aforementioned, should be considered when choosing a treatment option in the context of precision medicine.

Bronchial thermoplasty versus mepolizumab: Comparison of outcomes in a severe asthma clinic.

BT and interleukin-blocking monoclonal antibodies are both effective therapies for severe asthma, but there have been no direct comparisons between the two treatments. The aim of this study was to compare the efficacy and safety of BT and mepolizumab, in a real-world setting. Patients with severe asthma despite optimized inhaler therapy were drawn from a severe asthma clinic in a tertiary hospital. Every patient commencing therapy with BT or mepolizumab was prospectively included in a national registry. At predetermined assessment points over a 12-month period, assessments were made of ACQ, spirometry, oral corticosteroid requiring exacerbations, reliever medication and maintenance oral corticosteroid use. A total of 91 patients with severe asthma participated: mean ACQ score 3.5 ± 1.0, FEV1 51.4 ± 17.7%, maintenance oral steroids 48.3% and 11.5 ± 10.0 inhalations/day reliever therapy. Forty-seven patients received mepolizumab and 44 received BT. Baseline characteristics were similar except significantly higher blood eosinophil count in the mepolizumab group. At 12 months, there were no differences between treatment outcomes for ACQ (1.9 ± 1.3 mepolizumab vs 1.7 ± 1.3 BT), exacerbation rate (0.9 ± 1.1 vs 0.9 ± 1.5), reduction in reliever use (-6.3 ± 10.5 vs -5.0 ± 8.8 puffs/day) or reduction in oral corticosteroids (-3.3 ± 7.5 vs - 5.8 ± 6.7 mg/day). The FEV1 improved equally (160 ± 290 vs 150 ± 460 mL). Readmission or prolonged admission was observed in 18.2% of BT patients, whilst 25.5% of mepolizumab patients had discontinued treatment at 12 months, 14.9% due to an adverse event or non-compliance. The results suggest that BT is as efficacious as mepolizumab for the treatment of severe asthma.

Treatment Eligibility of Real-Life Mepolizumab-Treated Severe Asthma Patients

Patients with severe asthma not meeting the strict trial eligibility criteria for mepolizumab are now routinely treated with this biological in clinical practice, but it remains unclear whether these ineligible patients respond differently to mepolizumab treatment. This study investigated the extent and reasons for trial ineligibility of real-life, mepolizumab-treated patients with severe asthma and compared the characteristics of these patients with trial populations. Subsequently, therapeutic response in ineligible patients was assessed on the basis of oral corticosteroid (OCS) reduction. Trial eligibility, population differences, and therapeutic response were assessed using the baseline characteristics of mepolizumab-receiving patients with severe asthma treated in the Amsterdam University Medical Centres and OCS dose at 6 months for OCS-dependent patients extracted from patients' electronic health records. Eligibility criteria and population characteristics from trials investigating mepolizumab were extracted from their original publications. A total of 82.4% of 119 mepolizumab-receiving, real-life patients with severe asthma were ineligible for trial inclusion, wherein 42.9% and 39.5% were excluded on the basis of inclusion and exclusion criteria, respectively. The clinical care population was older, more often male and demonstrating a better lung function under lower OCS maintenance dosages in comparison with trial populations. A total of 50% of 66 ineligible, OCS-dependent mepolizumab-treated patients were able to reduce their maintenance OCS dosage to ≤5 mg prednisone/day. A large proportion of the real-life, mepolizumab-treated population with severe asthma would be excluded from trial participation, and significant differences in population characteristics exist. Regardless, a large fraction of ineligible patients in clinical care can reduce maintenance OCS dosage under mepolizumab therapy.

Belimumab may decrease flare rate and allow glucocorticoid withdrawal in lupus nephritis (including dialysis and transplanted patient).

Belimumab (Benlysta) is currently approved for the treatment of active Lupus despite standard therapy. Few data are available on the efficacy of this drug in lupus nephritis (LN). 17 LN female followed in two Nephrology Italian Unit received belimumab for a median period of 36months (range 6-42months). The indications were: arthralgia in 3 patients, cutaneous manifestations in 2, residual proteinuria in 8, and the need to reduce steroids for severe side effects in 4. Of interest, 1 patient started therapy during Peritoneal Dialysis and continued after kidney transplantation due to non-responsive arthralgias. Arthralgia and skin manifestations resolved in all patients. Proteinuria normalized in three patients and stabilized in all but one of the others. Steroids were indefinitely stopped in six patients (35%) and reduced to around 40% of the basal dosage in the other patients. During belimumab therapy, three extrarenal and one renal SLE flares were diagnosed accounting for a rate of renal flares of 0.02/patient/year. No major adverse events leading to therapy withdrawal occurred. Arthralgia resolved, immunological parameters improved and prednisone could be reduced within few months in the patient who started belimumab during peritoneal dialysis. After kidney transplantation belimumab was stopped but due to arthralgias unresponsive to standard immunosuppressive therapy it was restarted with success. Belimumab allows the achievement of complete response together with the withdrawal or the reduction of corticosteroids in almost all our patients. Of interest its satisfactory use in a patient in peritoneal dialysis and after kidney transplantation.

Corticosteroid reduction by addition of cetirizine and montelukast in biopsy-proven minimal-change nephrotic syndrome concomitant with allergic disorders

Recent reports suggest helper T-cell abnormalities in minimal-change nephrotic syndrome (MCNS), which often complicate allergic disorders that show a similar helper T-cell profile with Th2/Th17 predominance. However, the effect of anti-allergy therapy on MCNS remains unknown. This retrospective study included 51 patients with biopsy-proven MCNS recruited between November 2012 and October 2015, with follow-up through November 2017. We analyzed relapse and temporal daily corticosteroid dose with and without co-administration of histamine H1 receptor antagonist, cetirizine, and cysteinyl-leukotriene receptor antagonist, montelukast, as well as between baseline and after follow-up. Thirteen patients were treated with cetirizine and montelukast in addition to conventional therapy, whereas 38 patients were treated by conventional therapy only, consisting of corticosteroids and immunosuppressants. To adjust for baseline clinical characteristics, a 1:1 propensity score–matched model was applied. The clinical characteristics of the two groups after matching were similar at baseline. The treatment group showed a significant reduction in the lowest daily dose of oral prednisolone throughout the entire treatment course after the study compared to that of baseline (p < 0.025), which was not observed in the control group (p = 0.37), and showed significantly higher percentage of patients establishing corticosteroid-free state for the first time throughout the entire treatment course by addition of cetirizine and montelukast compared to the control group (p < 0.025). The study shows, for the first time, the steroid sparing effect of cetirizine and montelukast in addition to conventional treatment in MCNS patients with concomitant allergies.

PNS263 THE ROLE OF SURROGATES FOR PATIENT-RELEVANT ENDPOINTS IN THE EARLY BENEFIT ASSESSMENT IN GERMANY

Clinical trials conducted for regulatory approval mainly evaluate the efficacy of drugs by objective biomarkers rather than by patient-relevant endpoints. In the German early benefit assessment however, only patient-relevant endpoints are accepted. If surrogate endpoints are used instead, they need to be validated. We investigated the role of surrogate endpoints for early benefit assessment by the Institute for Quality and Efficiency in Health Care (IQWiG) and the Federal Joint Committee (G-BA). All early benefit assessments since the Act on the Reform of the Market for Medicinal Products (AMNOG) in 2011 until September 2018 were examined for surrogate endpoints in the manufacturer’s dossiers or defined as such during dossier assessment by IQWiG/G-BA. For all identified surrogate endpoints, the type of justification by the manufacturer and their final acceptance were evaluated. All 331 early benefit assessments were analyzed. In total 363 surrogate endpoints (multiple mentions possible) in 84 (25%) assessments were identified. Of these surrogate endpoints 9% were taken into account for the benefit assessment and 14% were accepted as surrogate or patient-relevant endpoint for the final decision by the G-BA. The following surrogate endpoints were accepted: virologic response and CD4 cell count in human immunodeficiency virus infection, reduction of oral corticosteroids in asthma and systemic lupus erythematosus, and HbA1c level in type 1 diabetes. However, reasons for acceptance sometimes differed from the manufacturer’s argumentation. Acceptance of surrogate endpoints for the added benefit decision is the exception. Although surrogate endpoints are commonly included in the manufacturer’s dossiers to claim benefit, only few manufacturers attempted to validate them. Instead, surrogates are typically either justified qualitatively or claimed to be patient-relevant endpoints. To increase the future acceptance of surrogate endpoints, more rigorous validation processes are necessary.

Prenatal metyrapone treatment modulates neonatal cerebrovascular structure, function, and vulnerability to mild hypoxic-ischemic injury.

This study explored the hypothesis that late gestational reduction of corticosteroids transforms the cerebrovasculature and modulates postnatal vulnerability to mild hypoxic-ischemic (HI) injury. Four groups of Sprague-Dawley neonates were studied: 1) Sham-Control, 2) Sham-MET, 3) HI-Control, and 4) HI-MET. Metyrapone (MET), a corticosteroid synthesis inhibitor, was administered via drinking water from gestational day 11 to term. In Shams, MET administration 1) decreased reactivity of the hypothalamic-pituitary-adrenal (HPA) axis to surgical trauma in postnatal day 9 (P9) pups by 37%, 2) promoted cerebrovascular contractile differentiation in middle cerebral arteries (MCAs), 3) decreased compliance ≤46% and increased depolarization-induced calcium mobilization in MCAs by 28%, 4) mildly increased hemispheric cerebral edema by 5%, decreased neuronal degeneration by 66%, and increased astroglial and microglial activation by 10- and 4-fold, respectively, and 5) increased righting reflex times by 29%. Regarding HI, metyrapone-induced fetal transformation 1) diminished reactivity of the HPA axis to HI-induced stress in P9/P10 pups, 2) enhanced HI-induced contractile dedifferentiation in MCAs, 3) lessened the effects of HI on MCA compliance and calcium mobilization, 4) decreased HI-induced neuronal injury but unmasked regional HI-induced depression of microglial activation, and 5) attenuated the negative effects of HI on open-field exploration but enhanced the detrimental effects of HI on negative geotaxis responses by 79%. Overall, corticosteroids during gestation appear essential for normal cerebrovascular development and glial quiescence but induce persistent changes that in neonates manifest beneficially as preservation of postischemic contractile differentiation but detrimentally as worsened ischemic cerebrovascular compliance, increased ischemic neuronal injury, and compromised neurobehavior.

Efficacy and Safety of HDM SLIT Tablet in Japanese Adults with Allergic Asthma

The standardized quality (SQ) house dust mite (HDM) sublingual immunotherapy (SLIT) tablet has demonstrated efficacy and safety for allergic asthma (AA) in European trials. To evaluate the efficacy and safety of SQ HDM SLIT tablet treatment for up to 19 months in Japanese adults with AA. In this randomized, double-blind, placebo-controlled trial, patients aged 18 to 64 years with AA were randomly assigned (1:1:1) to SQ HDM SLIT doses of 10,000 or 20,000 Japanese Allergy Unit or placebo. Subjects had Asthma Control Questionnaire score of 1.0 to 1.5 and daily inhaled corticosteroid use of 200 to 400 μg of fluticasone propionate at randomization. The primary end point was the time from randomization to the first asthma exacerbation as the inhaled corticosteroid dose was being reduced. Of the 826 randomized subjects, 693 (84%) completed the trial. No statistically significant differences between the active groups and the placebo group were observed for the primary or any other efficacy end points. However, post hoc analysis indicated a significant difference between the 20,000 Japanese Allergy Unit and placebo groups among subjects who used a short-acting β2-agonist during the baseline period (hazard ratio, 0.70; 95% CI, 0.48-1.00; P= .04997). No deaths or anaphylactic reactions were reported. Most adverse events were mild to moderate in severity. The trial demonstrated a favorable safety profile of the SQ HDM SLIT tablet in Japanese adult patients with AA. The treatment appeared to be efficacious in patients requiring rescue medication (ie, short-acting β2-agonist) at baseline in the efficacy assessment using asthma exacerbation during inhaled corticosteroid reduction (JapicCTI number 121847).

Cost-effectiveness of omalizumab for the treatment of moderate-to-severe uncontrolled allergic asthma in the United States

Objective: Uncontrolled asthma is associated with considerable clinical burden and costs to payers and patients. US economic models evaluating biologics using data from clinical trials demonstrate high incremental cost-effectiveness ratios (ICERs), but the cost-effectiveness based on real-world treatment patterns is unknown. This analysis used real-world evidence to assess the cost-effectiveness of adding omalizumab to standard of care (SOC).Methods: A Markov model was applied to track patients’ health states in 2-week cycles, comparing costs and treatment effects of SOC alone versus SOC + omalizumab over a lifetime (US payer perspective). Outcomes included exacerbation events, life years, quality-adjusted life years (QALYs), total costs, and an ICER. Patient characteristics, exacerbations, patient-reported outcomes, and work productivity were derived from the real-world PROSPERO (Prospective Study to Evaluate Predictors of Clinical Effectiveness in Response to Omalizumab) study. Published literature informed mortality, exacerbation-related disutility, and unit costs. Sensitivity analyses assessed model robustness.Results: Over a lifetime horizon, omalizumab was associated with an increase of 2.0 QALYs at a cost of $US 148,319 in patients with uncontrolled asthma (ICER of $75,319/QALY gained) and a reduction in exacerbations of 6.0 events/patient. Accounting for responder status improved the ICER ($70,505/QALY); incorporating indirect costs further reduced the ICER. One-way and multivariate sensitivity analyses confirmed that the base case outcome was robust to variation in inputs.Conclusions: Based on real-world outcomes, omalizumab may be cost-effective for uncontrolled asthma from the US payer perspective. Including broader evidence on treatment discontinuation, caregiver burden, and oral corticosteroid reduction from real-world studies may better reflect the effects and value of omalizumab for all healthcare stakeholders.

Reduction of oral corticosteroids in patients with severe eosinophilic asthma treated with Benralizumab: could it represent a marker of treatment efficacy?

ABSTRACTIntroduction: Subjects with severe Th2-high endotype usually respond to oral corticosteroids (OCS). However, they often require high dosages with incremental side effects and health-care costs. The advent of biological therapies provides an effective strategy to improve asthma control, as well as reduce OCS use. Various molecules have been developed, each targeting different pathways. We analyzed the two anti-IL-5 strategies, benralizumab and mepolizumab, based on pivotal trials (RCTs), mechanisms of action and their possible role on the steroid-sparing effect.Areas covered: This review analyzes the data from the benralizumab and mepolizumab RCTs, focusing on the advantages of each drug on clinical efficacy and the steroid-sparing effect.Expert opinion: Benralizumab may represent a promising therapeutic option in the treatment of eosinophilic asthma, due to its mechanism of action, which rapidly allows a reduction in the eosinophils’ number, and a greater steroid-sparing effect.

Long-term efficacy and tolerability of TNFα inhibitors in the treatment of non-infectious ocular inflammation: an 8-year prospective surveillance study

Background/AimTo report the efficacy and tolerability of antitumour necrosis factor-alpha therapy (TNF inhibitors [TNFi]) in the management of non-infectious ocular inflammation, including uveitis and scleritis, in adult patients over an...

Clinical Experience of Sirolimus Regarding Efficacy and Safety in Systemic Lupus Erythematosus.

New treatment options constitute unmet needs for patients diagnosed with systemic lupus erythematosus (SLE). Inhibition of the mammalian target of rapamycin (mTOR) pathway by sirolimus, a drug approved and in clinical use to prevent transplant rejection, has shown promising effects in lupus animal models as well as in patients with both antiphospholipid syndrome and SLE. Sirolimus inhibits antigen-induced T cell proliferation and increases the number of circulating regulatory T cells. Recently, sirolimus was tested in an open label phase 1/2 trial, including 43 patients with active SLE, resistant or intolerant to conventional medications. The results were encouraging showing a progressive improvement, including mucocutaneous and musculoskeletal manifestations. At our university unit, we have more than 16 years’ experience of sirolimus as treatment for non-renal manifestations of SLE. Herein, we retrospectively evaluated data on tolerance, dosage, affected organ systems, disease activity measures, corticosteroid reduction, concomitant immunosuppressive therapies, and patient-reported outcome measures (PROMs) such as pain intensity, fatigue, well-being and quality-of-life (QoL) in 27 Caucasian patients with mildly active SLE. Musculoskeletal manifestation was the main reason for sirolimus treatment followed by skin involvement and leukocytopenia. Mean time on sirolimus was 47.1 (range 2–140) months. Decreasing global disease activity was observed, as measured by the clinical SLE disease activity index-2000, with a mean reduction of 2.5 points (range -10 to 0) and a corresponding mean reduction of the physician’s global assessment (0–4) of 0.64 (range -2 to 0). The mean daily dose of corticosteroids (prednisolone) was reduced by 3.3 mg (-12.5 to 0). Non-significant trends toward improvements of QoL and pain intensity were found. Serious side-effects were not seen during sirolimus treatment, but early withdrawal due to nausea (n = 4) and non-serious infections (n = 2) appeared. This observational study, including longtime real-life use of sirolimus in SLE, is the largest to date and it essentially confirms the results of the recent phase 1/2 trial. Our data indicate that sirolimus is efficient in patients with musculoskeletal SLE manifestations, particularly arthritis and tendinitis. Further randomized controlled trials evaluating the potential benefits of sirolimus in SLE are warranted, but should aim to enroll patients with shorter disease duration, less accrued damage, and more diverse ethnicities.

Rituximab in the Treatment of Refractory Anti-HMGCR Immune-mediated Necrotizing Myopathy.

A pathogenic role of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) antibodies has been proposed. Our objective was to assess efficacy of rituximab (RTX) in anti-HMGCR immune-mediated necrotizing myopathy. All patients who had been treated with RTX were retrospectively reviewed to assess features and outcome. Three of 9 patients demonstrated stable or improved muscle strength ± decline in creatine kinase levels, or T2/short-tau inversion recovery hypersignal decrease on magnetic resonance imaging following RTX treatment. RTX permitted intravenous immunoglobulin discontinuation and corticosteroid reduction to low dose in 2 patients. One-third of patients with refractory anti-HMGCR had improved strength or other evidence of improved disease activity following RTX treatment.

Efficacy and Safety of Sarilumab for the Treatment of Posterior Segment Noninfectious Uveitis (SARIL-NIU):: The Phase 2 SATURN Study

To assess efficacy and safety of sarilumab, a human anti-interleukin-6 receptor antibody, for treatment of posterior segment noninfectious uveitis (NIU). Randomized, double-masked, placebo-controlled, phase 2 study. Fifty-eight patients (eyes) with noninfectious intermediate, posterior, or panuveitis. Eyes received treatment every 2 weeks for 16 weeks with subcutaneous sarilumab 200 mg or placebo. The primary end point was the proportion of patients with ≥2-step reduction in vitreous haze (VH) on the Miami scale or with a reduction of systemic corticosteroids (prednisolone or equivalent) to a dose of <10 mg/day at week 16. Primary end point was based on VH evaluation by a central reading center. Investigator evaluation of VH was a prespecified, planned secondary analysis. At week 16, proportion of patients taking sarilumab or placebo with ≥2-step reduction in VH or corticosteroid dose <10 mg/day was 46.1% vs. 30.0% (P= 0.2354) based on central reading center assessment ofVH and 64.0% vs. 35.0% (P= 0.0372) based on investigator assessment of VH, respectively. In the subgroup of eyes with VH grade ≥2 at baseline, the mean VH reduction from baseline to week 16 was significantly greater with sarilumab vs. placebo regardless of assessment by the central reading center (-2.1 [n= 11] vs.-1.7 [n= 3], respectively; P= 0.0255) or investigator (-2.5 [n= 19] vs.-1.2 [n= 11], respectively; P= 0.0170). The mean best-corrected visual acuity gain from baseline to week 16 was greater with sarilumab vs. placebo in the overall population (8.9 vs. 3.6 letters, respectively; P= 0.0333) and in the subgroup of eyes with central subfield thickness (CST) ≥300 μm at baseline (12.2 [n= 13] vs. 2.1 [n= 7] letters, respectively; P= 0.0517). Corresponding changes in CST were-46.8 vs.+2.6 μm (P= 0.0683) in the overall population and-112.5 [n= 13] vs.-1.8 [n= 6] μm (P= 0.1317) in the subgroup of eyes with CST ≥300 μm at baseline, respectively. The most common ocular adverse events were worsening of uveitis (0 [placebo] and 3 [sarilumab] patients) and retinal infiltrates (1 [placebo] and 2 [sarilumab] patients). Subcutaneous sarilumab may provide clinical benefits in the management of NIU of the posterior segment, especially in eyes with uveitic macular edema.

Efficacy and tolerability of a house dust mite allergoid in allergic bronchial asthma: a randomized dose-ranging trial.

This multicenter randomized placebo-controlled double-blind clinical trial investigated which maintenance dose shows the optimal benefit-risk ratio for subcutaneous immunotherapy with a Dermatophagoides pteronyssinus allergoid preparation. To evaluate four maintenance doses of the allergoid preparation versus placebo. The late-phase reaction of the intracutaneous test was chosen as efficacy parameter and minimal dose of fluticasone required for asthma control. A total of 146 adults with bronchial asthma were randomized. After subcutaneous immunotherapy, reductions in swelling size were greatest with 10,000therapeutic units (TU). The 18,000TU group showed the highest percentage of patients with fluticasone dose reduced to 0μg/day. The optimal dose of allergoid for the investigation in a confirmatory trial with inhaled corticosteroid reduction is 18,000TU.

Five-Year Graft Survival of Descemet Membrane Endothelial Keratoplasty (EK) versus Descemet Stripping EK and the Effect of Donor Sex Matching

To determine whether the reduced risk of immunologic rejection with Descemet membrane endothelial keratoplasty (DMEK) results in a 5-year survival advantage relative to Descemet stripping endothelial keratoplasty (DSEK) and to determine whether matching the donor and recipient sex affects the rejection episode and graft survival rates. Retrospective cohort study. Patients with Fuchs' endothelial corneal dystrophy treated with DSEK or DMEK. This study reviewed 2017 consecutive cases (1312 DSEK and 705 DMEK) performed by 13 surgeons between 2003 and 2012 and included the surgeons' first cases. Survival rates were calculated by Kaplan-Meier analysis. Immunologic rejection episodes, graft failure or replacement for any reason, and endothelial cell loss. The 5-year rejection episode rate was lower with DMEK (2.6% vs. 7.9% with DSEK, relative risk, 0.29; 95% confidence interval, 0.16-0.53) despite early reduction of topical corticosteroids in 25% of the DMEK cases. African Americans (n= 46) had a higher risk of rejection episodes than other races (relative risk, 4.4; 95% confidence interval, 2.0-9.6). The cumulative 5-year survival rate was 93% with DSEK and DMEK (P= 0.86). Forty-four DMEK and 69 DSEK grafts failed or were replaced within 5 years, but only 1 DMEK and 4 DSEK failures followed a rejection episode. Rejection episodes increased endothelial cell loss (P= 0.004) but were not a significant risk factor for graft failure within 5 years (P= 0.90). The mean 5-year endothelial cell loss was similar between DMEK (48%±19%) and DSEK (47%±19%) (P= 0.22). Graft rejection episode and survival rates were not significantly influenced by whether the sex of the donor matched that of the recipient (rejection episodes: P= 0.07 for female recipients and P= 0.33 for male recipients; graft survival: P=0.67 for female recipients and P= 0.17 for male recipients). Five-year graft survival was similar between DMEK and DSEK. Although DMEK had a significantly lower risk of immunologic rejection, rejection episodes rarely resulted in graft failure within 5 years with either procedure. Sex matching the donor and recipient provided no survival advantage with DSEK or DMEK.

Systemic Lupus Erythematosus (SLE) Responder Index response is associated with global benefit for patients with SLE.

A post-hoc analysis of pooled data from two Phase IIb trials (sifalimumab; NCT01283139, anifrolumab; NCT01438489) assessed the clinical significance of a Systemic Lupus Erythematosus (SLE) Responder Index (SRI(4)) response (Week 52) for 736 patients with moderate to severe SLE disease activity (study entry). SRI(4) responders achieved significantly greater improvements in clinical outcome measures (including percentages of patients with a ≥ 7-point reduction in SLE Disease Activity Index (SLEDAI)-2000 (2K), British Isles Lupus Assessment Group "A" or "2B" flare rate, and oral corticosteroid reduction to ≤7.5 mg/day; change from baseline in Physician's Global Assessment; and numbers of SLEDAI-2K organ domains with improvement), as well as in patient-reported outcomes (Patient's Global Assessment, Functional Assessment of Chronic Illness Therapy-Fatigue; Short-Form 36 Health Survey Physical Component Summary, Mental Component Summary, Vitality domain scores) vs. nonresponders. Of patients with abnormal serologies, SRI(4) responders had numerically greater improvements (baseline to Week 52) in anti-double-stranded DNA concentrations vs. nonresponders ( p = 0.051), but there were no differences in C3/C4 concentration changes between the two groups. These results confirm previous findings in a different cohort, indicating that an SRI(4) response is associated with global clinical benefit.

Efficacy of a House Dust Mite Sublingual Allergen Immunotherapy Tablet in Adults With Allergic Asthma: A Randomized Clinical Trial

JC Virchow, V Backer, P Kuna. JAMA. 2016;315(16):1715–1725 To evaluate the efficacy and adverse events of 2 doses of house dust mite (HDM) sublingual allergen immunotherapy (SLIT) versus a placebo for asthma exacerbations during inhaled corticosteroid (ICS) reduction in cases of unstable asthma. A total of 834 subjects (99% white, mean age of 33 years [range of 17–83 years], 48% women) were randomized 1:1:1 to receive 2 HDM tablet doses or a placebo. Six hundred ninety-three participants completed the trial. Dropout rates were similar among the 3 treatment groups. This was a double-blind, placebo-controlled, randomized trial comparing HDM SLIT using daily tablets in 2 doses (6 SQ-HDM or 12 SQ-HDM) with …

A multi-center randomized, controlled, open-label trial evaluating the effects of eosinophil-guided corticosteroid-sparing therapy in hospitalised patients with COPD exacerbations \u2013 The CORTICO steroid reduction in COPD (CORTICO-COP) study protocol

BackgroundThe most commonly applied treatment for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) is a 5-day course of high-dose systemic corticosteroids. However, this treatment has not been shown to reduce mortality and can potentially have serious side effects.Recent research has shown that, presumably, only a subgroup of COPD patients identifieable by blood eosinophil count benefit from a rescue course of prednisolone. By applying a biomarker-guided strategy, the aim of this study is to determine whether it is possible to reduce the use of systemic corticosteroids in AECOPD without influencing the outcome.MethodsThis is an ongoing prospective multicenter randomized controlled open label trial comprising 320 patients with AECOPD recruited from four hospitals in Denmark. The patients are randomized 1:1 to either standard care or eosinophil-guided corticosteroid-sparing therapy where prednisolone is not administered if the daily blood sampling reveals an eosinophil level below 0.3 × 109 cells/L. The primary endpoint is length of hospital stay within 14 days after recruitment. The secondary endpoints are treatment failure, 30-day mortality rate, COPD related re-admission rate, change in FEV1, and a number of adverse effect measures obtained within 3 months after the index hospitalisation date related to corticosteroid usage.DiscussionThis will be a very large RCT providing knowledge about the effectiveness of individualized biomarker-guided corticosteroid therapy in hospitalised patients with AECOPD.Trial registrationClinicaltrials.gov, NCT02857842, 02-august-2016. Clinicaltrialregister.eu: Classification Code: 10,010,953, 02-marts-2016.