Corticosteroid Dose Reduction Research Articles

A prospective evaluation of succinct prednisone tapering after brain tumor irradiation in dogs.

To ameliorate anticipated or ongoing neurological deficits, dogs undergoing brain tumor irradiation often are prescribed lengthy courses of prednisone PO during and after radiotherapy (RT). This practice can contribute to unwanted corticosteroid-associated morbidity and may be unnecessary. Determine whether long-term corticosteroid dependency can be minimized by use of succinct prednisone tapering. Fifty-five pet dogs undergoing brain tumor irradiation. Nineteen dogs were treated using a "rapid-taper" protocol wherein corticosteroid dose reduction began 0 to 20 days after completing RT. Outcomes were compared with a retrospectively studied control group ("slow-taper"; N = 36 dogs) in which corticosteroids were tapered more slowly according to individual clinician recommendations. Patient demographics were similar between groups. Mean time to lowest prednisone dose was 41 days postirradiation in the rapid-taper group and 117 days in the slow-taper group (P = .003). In the rapid-taper group, 15 of 19 dogs (84%) were completely tapered off prednisone, vs 18 of 36 (50%) in the slow-taper group (P = .04). Rates at which corticosteroids had to be reinstituted later were similar for the 2 groups (approximately 1 in 3 dogs). Adverse effect rates were similar for the 2 groups. Although no comparable questionnaire-derived data were available for the "slow-taper" group, overall and neurologic quality of life remained stable after RT in the rapid-taper group. For many dogs, lengthy courses of PO prednisone are avoidable after intracranial RT. Future efforts should aim to identify which dogs benefit most from accelerated prednisone tapering.

Oral and inhaled corticosteroid dose reductions with tezepelumab versus placebo in patients with severe, uncontrolled asthma from DESTINATION

The Global Initiative for Asthma recommends gradually stepping down treatments to the lowest oral/inhaled corticosteroid doses that control symptoms and exacerbations. Tezepelumab treatment enabled reductions in oral/inhaled corticosteroid doses versus placebo, while preserving asthma symptom control and lung function.

Real-World Data on Tezepelumab in Patients With Severe Asthma in Germany

Tezepelumab is a novel biologic blocking thymic stromal lymphopoetin, approved for severe asthma irrespective of biomarker levels or phenotype. To characterize a real-world tezepelumab patient cohort and the efficacy among various asthma phenotypes. We performed a retrospective, multicenter study on patients with severe asthma initiating tezepelumab. Clinical response was evaluated at 3 and 6 months. We included 129 patients with an average age of 52.5 ± 13.1 years, 59.7% were female. The majority (86.0%) had increased type 2 (T2) biomarkers, 68.2% an allergic and 31.8% an eosinophilic phenotype. 23.3% of patients were biologic-naive. 22 (18.2%) patients discontinued tezepelumab therapy owing to suspected side effects or insufficient efficacy. At 6 months' follow-up, median reduction in annualized exacerbation rate was-1 [25th percentile; 75% percentile {-2.9; 0.0}], the reduction of oral corticosteroid dose among patients with long-term oral corticosteroid therapy was -5 mg [-10; 0] and the Asthma Control Test (ACT) improved by 2 [0; 5] points. A treatment response according to Biologic Asthma Response Score of 80.8% was demonstrated. There were no significant differences in treatment response between T2-high versus T2-low, early- versus adult-onset and eosinophilic versus non-eosinophilic asthma. Prior treatment with other biologics was associated with inferior treatment response. In this real-life cohort, including a large proportion of patients with history of previous biologic use and encompassing various subgroups, the majority responded to tezepelumab. Our data further suggest a steroid-sparing effect of tezepelumab.

Palmoplantar Erythrodysesthesia: An Unusual Side Effect of Lenvatinib

Palmoplantar erythrodysesthesia also known as hand-foot syndrome is an intense, painful erythema of the palms and soles due to chemotherapeutic drugs. The most commonly implicated drugs are multi-kinase inhibitors such as sorafenib, sunitinib, doxorubicin, cytarabine, and docetaxel. The most effective management is withdrawal or reduction of drugs. Oral and topical corticosteroids and dimethyl sulfoxide are other treatment options. A 67-year-old male patient of hepatocellular carcinoma taking tablet lenvatinib presented with multiple tender erythematous plaques and patches over the bilateral palms and dorsum of the fingers after 1 month of initiation of therapy. The patient was successfully treated with dose reduction of lenvatinib and topical corticosteroids and is maintained on medium potency corticosteroid.

A phase II study of belumosudil for chronic graft-versus-host disease in patients who failed at least one line of systemic therapy in China

BackgroundChronic graft-versus-host disease (cGVHD) is an immune-related disorder that is the most common complication post-allogenic hematopoietic stem cell transplant. Corticosteroids with or without calcineurin inhibitors (CNIs) remain the mainstay of cGVHD treatment for first-line therapy. However, for many patients, cGVHD symptoms cannot be effectively managed and thus require second-line therapy. Currently, there is no approved treatment for second-line cGVHD treatment in China. In this study, belumosudil, a highly selective and potent rho-associated coiled-coil-containing protein kinase-2 inhibitor demonstrated to be effective for cGVHD in the United States and other Western countries, is investigated in patients with cGVHD in China for its overall benefit–risk balance.MethodsThis multicenter, open-label phase II study evaluated the safety, efficacy, and pharmacokinetics of oral belumosudil 200 mg once daily in cGVHD patients who had been treated with at least one line of systemic therapy in China. The primary endpoint was overall response rate (ORR); each individual patient’s response was assessed by the investigator using the 2014 National Institutes of Health consensus criteria. Secondary endpoints were duration of response (DOR), time to response (TTR), changes in Lee Symptom Scale (LSS) score, organ response rate, corticosteroid dose change, CNI dose change, failure-free survival, time-to-next-treatment, overall survival, and safety.ResultsThirty patients were enrolled in the study with a median follow-up time of 12.9 months. ORR was 73.3% (95% confidence interval: 54.1–87.7%) and all responders achieved partial response. Median DOR among responders was not reached and median TTR was 4.3 weeks (range: 3.9–48.1). Fifteen patients (50.0%) achieved clinically meaningful response in terms of reduction in LSS score by ≥ 7 points from baseline. Corticosteroid and CNI dose reductions were reported in 56.7% (17/30) and 35.0% (7/20) of patients, respectively. Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity, with 11 patients (36.7%) experiencing grade ≥ 3 TEAEs. The most common grade ≥ 3 TEAE was pneumonia (n = 5, 16.7%).ConclusionsBelumosudil treatment demonstrated a favorable benefit–risk balance in treating cGVHD patients who previously have had standard corticosteroid therapy in China where approved second-line setting is absent.Trial registrationClinicalTrials.gov identifier NCT04930562.

ONC201 (Dordaviprone) in Recurrent H3 K27M-Mutant Diffuse Midline Glioma.

Histone 3 (H3) K27M-mutant diffuse midline glioma (DMG) has a dismal prognosis with no established effective therapy beyond radiation. This integrated analysis evaluated single-agent ONC201 (dordaviprone), a first-in-class imipridone, in recurrent H3 K27M-mutant DMG. Fifty patients (pediatric, n = 4; adult, n = 46) with recurrent H3 K27M-mutant DMG who received oral ONC201 monotherapy in four clinical trials or one expanded access protocol were included. Eligible patients had measurable disease by Response Assessment in Neuro-Oncology (RANO) high-grade glioma (HGG) criteria and performance score (PS) ≥60 and were ≥90 days from radiation; pontine and spinal tumors were ineligible. The primary end point was overall response rate (ORR) by RANO-HGG criteria. Secondary end points included duration of response (DOR), time to response (TTR), corticosteroid response, PS response, and ORR by RANO low-grade glioma (LGG) criteria. Radiographic end points were assessed by dual-reader, blinded independent central review. The ORR (RANO-HGG) was 20.0% (95% CI, 10.0 to 33.7). The median TTR was 8.3 months (range, 1.9-15.9); the median DOR was 11.2 months (95% CI, 3.8 to not reached). The ORR by combined RANO-HGG/LGG criteria was 30.0% (95% CI, 17.9 to 44.6). A ≥50% corticosteroid dose reduction occurred in 7 of 15 evaluable patients (46.7% [95% CI, 21.3 to 73.4]); PS improvement occurred in 6 of 34 evaluable patients (20.6% [95% CI, 8.7 to 37.9]). Grade 3 treatment-related treatment-emergent adverse events (TR-TEAEs) occurred in 20.0% of patients; the most common was fatigue (n = 5; 10%); no grade 4 TR-TEAEs, deaths, or discontinuations occurred. ONC201 monotherapy was well tolerated and exhibited durable and clinically meaningful efficacy in recurrent H3 K27M-mutant DMG.

The Association of Oleic Acid and Dexamethasone Acetate into Nanocapsules Enables a Reduction in the Effective Corticosteroid Dose in a UVB Radiation-Induced Sunburn Model in Mice.

Dexamethasone has a high anti-inflammatory efficacy in treating skin inflammation. However, its use is related to the rebound effect, rosacea, purple, and increased blood glucose levels. Nanotechnology approaches have emerged as strategies for drug delivery due to their advantages in improving therapeutic effects. To reduce dexamethasone-related adverse effects and improve the anti-inflammatory efficacy of treatments, we developed nanocarriers containing this corticosteroid and oleic acid. Nanocapsules and nanoemulsion presented dexamethasone content close to the theoretical value and controlled dexamethasone release in an in vitro assay. Gellan gum-based hydrogels were successfully prepared to employ the nanostructured systems. A permeation study employing porcine skin showed that hydrogels containing non-nanoencapsulated dexamethasone (0.025%) plus oleic acid (3%) or oleic acid (3%) plus dexamethasone (0.025%)-loaded nanocapsules provided a higher amount of dexamethasone in the epidermis compared to non-nanoencapsulated dexamethasone (0.5%). Hydrogels containing oleic acid plus dexamethasone-loaded nanocapsules effectively inhibited mice ear edema (with inhibitions of 89.26 ± 3.77% and 85.11 ± 2.88%, respectively) and inflammatory cell infiltration (with inhibitions of 49.58 ± 4.29% and 27.60 ± 11.70%, respectively). Importantly, the dexamethasone dose employed in hydrogels containing the nanocapsules that effectively inhibited ear edema and cell infiltration was 20-fold lower (0.025%) than that of non-nanoencapsulated dexamethasone (0.5%). Additionally, no adverse effects were observed in preliminary toxicity tests. Our study suggests that nanostructured hydrogel containing a reduced effective dose of dexamethasone could be a promising therapeutic alternative to treat inflammatory disorders with reduced or absent adverse effects. Additionally, testing our formulation in a clinical study on patients with skin inflammatory diseases would be very important to validate our study.

Very long-term data on patients with severe eosinophilic asthma treated with mepolizumab: a case series.

Patients with severe asthma are often dependent on oral corticosteroids (OCS) and have frequent exacerbations. This article aims to report very long-term data of patients with severe eosinophilic asthma assessing asthma control, lung function, inhaled corticosteroid (ICS) dose reduction, and clinical and biological parameters of patients treated with mepolizumab. Four cases of adult patients with severe eosinophilic asthma who were treated for 60 months or more with mepolizumab 100 mg/4 weeks, leading to the stable discontinuation of OCS, are presented. ICS dose, OCS dose and withdrawal date, lung function, eosinophil count, fractional exhaled nitric oxide, and asthma control test were recorded as well as exacerbations in the 12 months before commencing mepolizumab and in the 12 months before the last follow-up visit. Three of the patients were men, median age was 52.5 years (range 79-53), median length of asthma before mepolizumab start was 67.5 months (range 24-240), three had chronic rhinosinusitis without nasal polyposis and two were atopic. All had eosinophil counts >300 cells/μL at baseline. The median follow-up was 73.5 months (range 71-74), and OCS withdrawal from baseline occurred after a median of 13 months of mepolizumab treatment (range 12-39). A substantial reduction of ICS treatment was registered as well as improvement in asthma control test, fractional exhaled nitric oxide and functional parameters, and a significant reduction of exacerbations in the last 12 months before last visit was observed as compared to the 12 months before baseline (from a median of 4 (range 3-6) to 0; p=0.0286). Mepolizumab could be a 'disease-modifying' agent, with high tolerability and a good efficacy profile in the long term.

Eosinophil to lymphocyte ratio may predict OCS reduction and change in quality of life (AQLQ) resulting from asthma biological treatment

Objectives Simple clinical parameters that could be helpful in choice of monoclonal antibodies and prediction of their effectiveness are being sought. The aim was to assess if neutrophil-to-lymphocyte, eosinophil-to-lymphocyte and platelet-to-lymphocyte ratios may predict outcomes of biologic therapy for severe asthma. Methods Retrospective, single-center study including severe asthma patients treated with three different biologics. The blood ratios were assessed at initiation of treatment (point 0) and after six months (point 1). The chi-square test was used to analyze differences in nominal variables. Quantitative variables were compared by Student’s t-test, Mann–Whitney U or Wilcoxon signed-rank tests. Results 53 patients with severe asthma were included, among them 21 patients (40%) treated with omalizumab and 32 patients (60%) with mepolizumab or benralizumab. Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios did not change during six-month-course of biological treatment. Eosinophil-to-lymphocyte ratio was higher at the point 0 (p = 0.016) in the group treated with anti-eosinophils than in the omalizumab group and lower at the point 1 (p = 0.006). In the anti-eosinophil group this ratio decreased between points 0 and 1 (p < 0.001). In the omalizumab group there was an inverse correlation between the initial ratio and oral corticosteroid dose reduction (rs = −0,67). In the a/eos group there were significant correlations between initial ratio and age (rs = 0.36), and ACQ (rs = −0.4) and ACQ (rs = 0.41) measured at the point 1. Conclusions Pretreatment eosinophil-to-lymphocyte ratio may predict oral corticosteroid dose reduction resulting from omalizumab treatment and change in quality of life and asthma control resulting from anti-IL-5 and IL-5R treatment.

A Single-center, Real-world Experience of Chronic GVHD Treatment Using Ibrutinib, Imatinib, and Ruxolitinib and its Treatment Outcomes.

Chronic graft-versus-host disease (cGVHD) is a common cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Tyrosine kinase inhibitors (TKIs), including ruxolitinib, imatinib, and ibrutinib, have shown promising efficacy in cGVHD treatment. A total of 43 patients who developed cGVHD and received at least one line of TKI therapy for cGVHD treatment were evaluated retrospectively. The overall response, clinical benefit (CB), corticosteroid dose reduction, failure-free survival (FFS), and overall survival (OS) were assessed. A total of 62 lines of TKI therapy were evaluated, including ruxolitinib (n = 18), ibrutinib (n = 13), and imatinib (n = 31). With a 12-month median follow-up duration, 19/58 (32.8%), 20/41 (48.7%), and 17/29 (58.6%) responded to TKI therapy at 3, 6, and 12 months, respectively. The CB was observed in 80% of patients over time, allowing prednisone dose reduction in all 3 TKIs. The FFS rate at 12 months was higher in the imatinib (71%) and ruxolitinib groups (67%) than in the ibrutinib group (46%), while the OS rate at 12 months was similar among the three groups at 96%-100% in patients. In the sclerotic GVHD patient subgroup (n = 39), the overall response rate gradually increased over time. Ruxolitinib appeared to be as effective as imatinib and gradually improved the photographic range of motion score in sclerotic GVHD patients. TKI drugs ruxolitinib, imatinib, and Ibrutinib are effective and feasible for cGVHD treatment. Ruxolitinib is as effective as imatinib for sclerotic GVHD.

Reduction of disease activity, corticosteroids use, and healthcare resource utilisation in patients with systemic lupus erythematosus treated with belimumab in clinical practice settings: OBSErve Spain multicentre study

Introduction and objectivesThis OBSErve Spain study, a part of the international OBSErve programme, evaluated belimumab real-world use and effectiveness following 6 months of treatment in patients with active systemic lupus erythematosus (SLE) in clinical practice in Spain. Materials and methodsIn this retrospective, observational study (GSK Study 200883), eligible patients with SLE receiving intravenous belimumab (10mg/kg) had their disease activity (physician assessed), SELENA-SLEDAI scores, corticosteroid use, and healthcare resource utilisation (HCRU), assessed after 6 months of treatment versus index (belimumab initiation) or 6 months pre-index. ResultsOverall, 64 patients initiated belimumab, mainly due to ineffectiveness of previous treatments (78.1%) and to reduce corticosteroid use (57.8%). Following 6 months of treatment, 73.4% of patients achieved ≥20% overall clinical improvement, while only 3.1% of patients worsened. Mean (standard deviation, SD) SELENA-SLEDAI score decreased from 10.1 (6.2) at index to 4.5 (3.7) 6 months post-index. HCRU decreased from 6 months pre-index to 6 months post-index, with fewer hospitalisations (10.9% vs 4.7% patients) and ER visits (23.4% vs 9.4% patients). Mean (SD) corticosteroid dose decreased from 14.5 (12.5)mg/day at index to 6.4 (5.1)mg/day 6 months post-index. ConclusionsPatients with SLE receiving belimumab for 6 months in real-world clinical practice in Spain experienced clinical improvements and a reduction in HCRU and corticosteroid dose.

Comparing bronchial thermoplasty with biologicals for severe asthma: Systematic review and network meta-analysis

BackgroundBronchial thermoplasty (BT) has shown favorable safety and efficacy in several randomized controlled trials (RCTs), but has not been directly compared to biological therapies. MethodsElectronic literature searches were performed on PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials, to retrieve RCTs of BT or FDA-approved biologicals against controls in patients with severe asthma. Six outcomes were analyzed: Asthma Control Questionnaire (ACQ), Asthma Quality of Life Questionnaire (AQLQ), the number of patients experiencing ≥1 asthma exacerbation, annualized exacerbation rate ratio (AERR), oral corticosteroid dose reduction (OCDR), and morning peak expiratory flow rate (amPEF). Random-effects, Frequentist network meta-analysis (NMA) were performed, and therapies were ranked using P-scores. ResultsTwenty-nine RCTs (15,547 patients) were included. Fewer patients treated with BT experienced ≥1 asthma exacerbation (risk ratio [RR] = 0.66, 95%CI = 0.45–0.98) compared to control. AERR of BT versus control was non-significant, but significant improvements in ACQ score (mean difference [MD] −0.41, 95%CI -0.63 to −0.20), AQLQ score (MD = 0.54, 95%CI = 0.30–0.77), amPEF and OCDR were found. No significant differences between BT and biologics were seen across indirect comparisons of all studies. ConclusionsDespite the lack of head-to-head comparative trials, this NMA suggests that BT is non-inferior to biologicals in terms of quality-of-life scores, and represents a promising alternative for patients with severe asthma.

Can Simvastatin Reduce the Need for Immunomodulatory Drugs to Treat Uveitis?: A Prospective, Randomized, Placebo-Controlled Trial

To assess the efficacy of simvastatin 80 mg/day versus placebo in patients with noninfectious nonanterior uveitis receiving prednisolone ≥ 10 mg/day. Randomized, double-masked, controlled trial. Adult patients with noninfectious nonanterior uveitis on oral prednisolone dose of ≥ 10 mg/day. Patients were randomly assigned at a 1:1 ratio to receive either simvastatin 80 mg/day or placebo. A total of 32 patients were enrolled (16 in each arm), all of whom completed the primary end point, and 21 reached the 2-year visit (secondary end points). The primary end point was mean reduction in the daily prednisolone dose at 12 months follow-up. Secondary end points were mean reduction in prednisolone dose at 24 months, percent of patients with a reduction in second-line immunomodulatory agents, time to disease relapse, and adverse events. Our results show that simvastatin 80 mg/day did not have a significant corticosteroid-sparing effect at 12 months (estimate: 3.62; 95% confidence interval [CI]:-8.15 to 15.38; P= 0.54). There was no significant difference between the groups with regard to prednisolone dose or change in dose at 12 and 24 months. There was no difference between the 2 groups in percent of patients with reduction in second-line agent by 24 months. Among patients who achieved disease quiescence, the median time to first relapse was longer for those receiving simvastatin (38 weeks, 95% CI: 14-54) than placebo (14 weeks, 95% CI: 12-52), although this was not statistically significant. There was no significant difference in adverse events or serious adverse events between the 2 groups. Simvastatin 80 mg/day did not have an effect on the dose reduction of corticosteroids or conventional immunomodulatory drugs at 1 and 2 years. The results suggest that it may extend the time to disease relapse among those who achieve disease quiescence. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Omalizumab ameliorates extrarespiratory symptoms in patients with aspirin-exacerbated respiratory disease

Omalizumab, an anti-immunoglobulin E antibody, has clinical efficacy against respiratory symptoms of aspirin-exacerbated respiratory disease (AERD). However, some patients with AERD also present with extra-respiratory (chest, gastrointestinal, and/or cutaneous) symptoms, which are resistant to conventional treatment but can be alleviated by systemic corticosteroids. To evaluate the efficacy of omalizumab on extra-respiratory symptoms related to AERD. In Study 1, 27 consecutive patients with AERD initially prescribed omalizumab at Sagamihara National Hospital between July 2009 and March 2019 were studied retrospectively. The frequency of exacerbations of AERD-related extra-respiratory symptoms was compared before and after the initiation of omalizumab treatment. In Study 2, we reported three AERD cases with aspirin challenge-induced extra-respiratory symptoms among patients studied in our previous randomized trial (registration number: UMIN000018777), which evaluated the effects of omalizumab on hypersensitivity reactions during aspirin challenge to AERD patients. The extra-respiratory symptoms induced during the aspirin challenge were compared between the placebo and omalizumab phases. In Study 1, omalizumab treatment was associated with a decrease in the frequency of exacerbation of chest pain (n [%] of patients with exacerbation frequency ≥1 time per year, 6 [22.2%] vs. 0 [0%]; P<0.001), gastrointestinal symptoms (9 [33.3%] vs. 2 [7.4%]; P=0.016), and cutaneous symptoms (16 [59.3%] vs. 2 [7.4%]; P<0.001), even under conditions of a treatment-related reduction in systemic corticosteroid dose. Omalizumab also attenuated all the extra-respiratory symptoms during the aspirin challenge in Study 2. Omalizumab ameliorated the extra-respiratory symptoms at baseline (without aspirin exposure) and during aspirin challenge.

Clinical response to benralizumab can be predicted by combining clinical outcomes at 3 months with baseline characteristics.

Benralizumab is highly effective in many, but not all, patients with severe asthma. Baseline characteristics alone are insufficient to predict an individual's probability of long-term benralizumab response. The objectives of the present study were to: 1) study whether parameters at 3 months, in addition to baseline characteristics, contribute to the prediction of benralizumab response at 1 year; and 2) develop an easy-to-use prediction tool to assess an individual's probability of long-term response. We assessed the effect of benralizumab treatment in 192 patients from the Dutch severe asthma registry (RAPSODI). To investigate predictors of long-term benralizumab response (≥50% reduction in maintenance oral corticosteroid (OCS) dose or annual exacerbation frequency) we used logistic regression, including baseline characteristics and 3-month Asthma Control Questionnaire (ACQ-6) score and maintenance OCS dose. Benralizumab treatment significantly improved several clinical outcomes, and 144 (75%) patients were classified as long-term responders. Response prediction improved significantly when 3-month outcomes were added to a predictive model with baseline characteristics only (area under the receiver-operating characteristic (AUROC) 0.85 versus 0.72, p=0.001). Based on this model, a prediction tool using sex, prior biologic use, baseline blood eosinophils, forced expiratory volume in 1 s, and at 3 months OCS dose and ACQ-6 was developed which classified patients into three categories with increasing probability of long-term response (95% CI): 25% (3-65%), 67% (57-77%) and 97% (91-99%), respectively. In addition to baseline characteristics, treatment outcomes at 3 months contribute to the prediction of benralizumab response at 1 year in patients with severe eosinophilic asthma. Prediction tools as proposed in this study may help physicians optimise the use of costly biologics.

Energy Trial in Warm Autoimmune Hemolytic Anemia (wAIHA): Design of a Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Nipocalimab, an FcRn Blocker

Background: Warm autoimmune hemolytic anemia (wAIHA) is a rare condition characterized by the premature destruction of red blood cells (RBCs) mainly in the presence of pathogenic immunoglobulin G (IgG) autoantibodies that preferentially bind to RBCs at 37°C, resulting in extravascular hemolysis of these RBCs in the spleen (or liver). Patients with wAIHA can experience acute or chronic worsening of anemia, increased risk of thromboembolic events, and premature death. Innovative targeted therapies that address the underlying pathogenesis of wAIHA are needed, as there is currently no approved treatment for this disease. Nipocalimab is a high affinity, fully human, aglycosylated, effectorless IgG1 monoclonal antibody that targets the neonatal Fc receptor (FcRn) to lower circulating IgG levels, including pathogenic autoantibodies. Nipocalimab is being evaluated across multiple IgG-mediated diseases. A completed phase 2 study in patients with generalized myasthenia gravis demonstrated rapid, durable total serum IgG and pathogenic IgG autoantibody reductions and meaningful clinical response [Guptill J, et al. AAN 2021. Presentation 2157]. Aim: Describe the rationale and study design of ENERGY, an ongoing, adaptive, phase 2/3 multicenter, randomized, double-blind, placebo-controlled study that will evaluate the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of nipocalimab compared with placebo in patients with wAIHA (NCT04119050). Methods: Subjects ≥18 years of age who have been diagnosed with primary or secondary wAIHA and are currently receiving treatment for wAIHA or have previously received treatment for wAIHA will be included in the study. Subjects with cold antibody AIHA, cold agglutinin syndrome, mixed type (i.e., warm and cold) AIHA, or paroxysmal cold hemoglobinuria will be excluded. Stable doses of corticosteroids or immunosuppressants will be allowed. Approximately 111 patients will be randomized 1:1:1 to receive nipocalimab at two different dose schedules or placebo. Following completion of 24 weeks of double-blind treatment, patients may enter an open-label extension period to receive nipocalimab for 144 weeks with a follow-up period of 6 weeks after last assessment. Results: ENERGY will include approximately 160 sites across 19 countries, including Brazil, Canada, China, Czech, Egypt, France, Germany, Greece, Hungary, Japan, Israel, Malaysia, Netherlands, Italy, Poland, South Korea, Spain, the United Kingdom, and the United States. The primary endpoint is percentage of participants achieving durable response of improvement in hemoglobin (Hgb). The secondary endpoints include change from baseline in the total score from the Functional Assessment of Chronic Illness Therapy-Fatigue Scale, corticosteroid dose reduction from baseline, and normalization of hemolytic markers. Conclusion/Summary: The results of ENERGY have the potential to identify a novel treatment option to address the significant unmet needs of patients with wAIHA. Enrollment is ongoing in this clinical trial.

The Efficacy and Safety of Ruxolitinib in Steroid-Refractory Graft-Versus-Host Disease in Chinese Patients: Systematic Review and Meta-Analysis

Introduction Graft-versus-host disease (GvHD) is the most common long-term complication and also a major cause of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT), frequently involving skin, digestive tract, liver, and lung. Corticosteroids are the first-line treatment and immunosuppressants are usually the second-line treatment for GvHD, but they have limited efficacy for steroid-refractory-GvHD (SR-GvHD). Ruxolitinib an oral tyrosine kinase-Janus kinase (JAK) 1/2 inhibitor was approved by FDA for the treatment of SR-GvHD. As direct head-to-head trials of Ruxolitinib in Chinese patients are not available, it was necessary to carry out systematic review and meta-analysis (SR&MA) to evaluate the efficacy and safety of Ruxolitinib in Chinese patients with SR-GvHD. Methods The present study was performed in accordance with the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) statement. We searched the MEDLINE, EMBASE, Cochrane Library and relevant databases for clinical and observational studies evaluating the efficacy and safety of Ruxolitinib in Chinese patients with confirmed SR-GvHD from inception to December 2021. Data from the included studies was extracted in predefined extraction grid and study quality was evaluated to identify risk of bias. Outcomes of interest included overall objective response rate (ORR), complete response (CR), partial response (PR), non-response (NR); proportion of hormone reduction and withdrawal; overall survival (OS), mortality, safety, and tolerability. Meta-analysis of the included studies was performed using the Cochrane Collaboration recommended systematic review method and software (Stata 16). Results A total of 19 case series and cohorts with 775 patients with age between 0.9 to 64 years were included in the study. Ruxolitinib was administered at a dose of 10 to 20 mg/day, of which 561 (72.4%) received 5 to 10 mg bid. Among 339 patients with acute GvHD and 431 patients with chronic GvHD included in 13 studies, ORR, CR, PR, and NR were 86% and 77%, 56% and 36%, 28% and 41% and 14% and 21%, respectively (Table 1). The ORR in the subgroup of patients with skin, gastrointestinal and liver-GvHD was the highest among patients with aGvHD and cGvHD (85% and 84%, 73% and 71%, 69% and 70%) respectively. Four studies described a dose reduction or discontinuation of Corticosteroids: aGvHD (46.51% and 34.88%) and cGvHD (28.24% and 36.86%), respectively (Figure 1). Twelve months OS was reported in four studies, including 404 patients, 179 with aGvHD and 225 with cGvHD. Overall, 12-month survival was 71% (95% CI 63% -79%); aGvHD: 66% (95% CI 56% -76%) and cGvHD: 76% (95% CI 56% -76%), respectively. Among 579 patients with SR-GvHD; 298 with aGvHD and 281 with cGvHD, resulting in an overall mortality rate of 26% (95% CI 19% -34%); aGvHD: 31% (95% CI 21% -42%) and cGvHD: 21% (95% CI 12% -32%) respectively. Eighteen studies reported 760 adverse reactions, and 287 viral infections (36.0%) and 269 cytopenias (34.7%) were the most common adverse reactions. Briefly, Cytomegalovirus infection (18.7%) and Epstein-Barr virus infection (10.8%), thrombocytopenia (12.9%) and hemoglobin (11.1%) were the most frequent Cytopenias. Conclusion Results of the meta-analysis showed that Ruxolitinib could have a positive effect in the treatment of SR-GvHD in the Chinese population. Ruxolitinib was able to significantly reduce or discontinue steroid dosage in patients with SR-GvHD. The adverse drug reactions were mainly cytopenias and viral infections consistent with observations of the REACH studies. Ruxolitinib was generally well tolerated, and no new safety signals were observed. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CLINICAL OUTCOMES AND EMERGENCY HEALTH CARE UTILIZATION IN PATIENTS WITH SEVERE ASTHMA WHO CONTINUED, SWITCHED, OR STOPPED BIOLOGIC THERAPY: RESULTS FROM THE CLEAR STUDY

CLINICAL OUTCOMES AND EMERGENCY HEALTH CARE UTILIZATION IN PATIENTS WITH SEVERE ASTHMA WHO CONTINUED, SWITCHED, OR STOPPED BIOLOGIC THERAPY: RESULTS FROM THE CLEAR STUDY

The concise review of etiology, pathology, and treatment strategy of polyarteritis nodosa

Polyarteritis nodosa (PAN) is a necrotizing vasculitis that targets medium-sized muscular arteries and can involve small-sized arteries. The pathogenesis of classic PAN remains unclear, except for secondary PAN or vasculitis that is indistinguishable from PAN due to genetic abnormalities such as deficiency of adenosine deaminase 2. The histopathological characters of PAN change over time from the onset. The type of remission induction therapy to be adopted depends on the disease severity. When it results in remission, corticosteroid dose reduction will begin and will be shifted to remission maintenance therapy.

Airway autoimmunity, asthma exacerbations, and response to biologics.

Biologic therapies in asthma are indicated in severe disease, and they are directed against specific inflammatory modulators that contribute to pathogenesis and severity. Currently approved biologics target T2 cytokines (IgE, IL-5, IL-4/IL-13, and TLSP) and have demonstrated efficacy in clinical outcomes such as exacerbation rate and oral corticosteroid dose reductions, blood and airway eosinophil depletion, and lung function improvement. However, a proportion of these patients may show inadequate responses to biologics, with either initial lack of improvement or clinical and functional worsening after an optimal initial response. Exacerbations while on a biologic may be due to several reasons, including imprecise identification of the dominant effector pathway contributing to severity, additional inflammatory pathways that are not targeted by the biologic, inaccuracies of the biomarker used to guide therapy, inadequate dosing schedules, intercurrent airway infections, anti-drug neutralizing antibodies, and a novel phenomenon of autoimmune responses in the airways interfering with the effectiveness of the monoclonal antibodies. This review, illustrated using case scenarios, describes the underpinnings of airway autoimmune responses in driving exacerbations while patients are being treated with biologics, device a strategy to evaluate such exacerbations, an algorithm to switch between biologics, and perhaps to consider two biologics concurrently.