Corticosteroid Dose Reduction Research Articles

Bevacizumab for pediatric radiation necrosis.

Radiation necrosis is a frequent complication occurring after the treatment of pediatric brain tumors; however, treatment options remain a challenge. Bevacizumab is an anti-VEGF monoclonal antibody that has been shown in small adult cohorts to confer a benefit, specifically a reduction in steroid usage, but its use in children has not been well described. We describe our experience with bevacizumab use for symptomatic radiation necrosis at 5 institutions including patients treated after both initial irradiation and reirradiation. We identified 26 patients treated with bevacizumab for symptomatic radiation necrosis, with a wide range of underlying diagnoses. The average age at diagnosis of radiation necrosis was 10.7 years, with a median time between the last dose of radiation and the presentation of radiation necrosis of 3.8 months (range, 0.6-110 months). Overall, we observed that 13 of 26 patients (50%) had an objective clinical improvement, with only 1 patient suffering from significant hypertension. Radiological improvement, defined as reduced T2/fluid-attenuated inversion recovery signal and mass effect, was observed in 50% of patients; however, this did not completely overlap with clinical response. Both early and late radiation necrosis responded equally well to bevacizumab therapy. Overall, bevacizumab was very well tolerated, permitting a reduction of corticosteroid dose and/or duration in the majority of patients. Bevacizumab appears to be effective and well-tolerated in children as treatment for symptomatic radiation necrosis and warrants more robust study in the context of controlled clinical trials.

Systematic Assessment for Difficult and Severe Asthma Improves Outcomes and Halves Oral Corticosteroid Burden Independent of Monoclonal Biologic Use

Guidelines endorse systematic assessment for severe asthma, with data indicating benefit across multiple outcome domains. We examined which patients respond to systematic assessment and whether oral corticosteroid burden can be decreased independent of monoclonal biologic use. Specialist-referred patients are assessed systematically for difficult asthma at our center. We undertook a responder analysis for improvements in the domains of symptom control, quality of life, exacerbations, and airflow obstruction, assessed 6 months after initial assessment. Multivariate analyses were performed for each domain to identify predictors of response. Changes in oral corticosteroid burden were also measured, stratified by monoclonal biologics commenced during assessment. Among 161 patients assessed systematically, 64% had a reduction in exacerbations, 54% achieved minimum clinically important differences for both symptom control and quality of life, and 40% increased their forced expiratory volume in 1 second by ≥100 mL. Altogether, 87% of patients with asthma improved in at least 1 domain. The most consistent predictor of response across domains was poorer baseline asthma status. There was a substantial reduction in mean chronic oral corticosteroid dose (11-5 mg, n= 46, P < .001), even after excluding 7 patients commenced on monoclonal biologics (11-5.6 mg, n= 39, P < .001). Almost 90% of patients undergoing systematic assessment for difficult asthma improve significantly in at least 1 key asthma outcome, with few reliable predictors of response. The halving of oral corticosteroid burden during systematic assessment is independent of, and comparable in magnitude with, that achieved by monoclonal biologics.

ACR/ARP 2019

Anifrolumab, a human monoclonal antibody targeting the type I IFN receptor subunit 1, is beneficial for patients with moderate to severe systemic lupus erythematosus (SLE) who have active disease despite receiving standard therapy. Richard Furie (Northwell Health, USA) and Eric Morand (Monash University, Australia) presented findings from two phase 3 trials in SLE. In TULIP-1, patients were randomly assigned (2:1:2) to receive placebo (n=184), anifrolumab 150 mg (n=93), or anifrolumab 300 mg (n=180) intravenously every 4 weeks for 48 weeks. In TULIP-2, patients were randomly assigned (1:1) to receive either placebo (n=182) or anifrolumab 300 mg (n=180) on the same schedule. In both trials, standard-of-care treatment continued except for oral corticosteroid tapering for patients receiving 10 mg/day or more prednisone or equivalent at baseline. TULIP-1 did not meet its primary endpoint (SLE responder index-4 at week 52), with 65 (36%) of 180 patients in the 300 mg anifrolumab group achieving SRI-4 versus 74 (40%) of 184 in the placebo group. However, more patients in the anifrolumab group achieved a reduction in oral corticosteroid dose and a BILAG-based composite lupus assessment (BICLA) response, suggesting potential clinical benefit of the drug. In TULIP-2, anifrolumab was superior to placebo for BICLA response at week 52 (the primary endpoint), with 86 (48%) of 180 patients in the anifrolumab group and 57 (31%) of 182 in the placebo group achieving BICLA response. The safety profile of anifrolumab's safety was similar to that observed in phase 2 trials. Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trialThe primary endpoint was not reached. However, several secondary endpoints, including reduction in oral corticosteroid dose, CLASI responses, and BICLA responses, suggest clinical benefit of anifrolumab compared with placebo. Conclusive evidence for the efficacy of anifrolumab awaits further phase 3 trial data. Despite the inherent limitations of a 1-year phase 3 study, such as incomplete knowledge of applicability to the general population and scarce detection of rare safety signals, in addition to complications from prespecified restricted medication rules, our results suggest that anifrolumab might have the potential to provide a treatment option for patients who have active SLE while receiving standard therapy. Full-Text PDF

Reduction of corticosteroid use in outpatient treatment of exacerbated COPD\xa0- Study protocol for a randomized, double-blind, non-inferiority study, (The RECUT-trial)

BackgroundChronic obstructive pulmonary disease (COPD) is a major public health issue affecting approximately 4% to 7% of the Swiss population. According to current inpatient guidelines, systemic corticosteroids are important in the treatment of acute COPD exacerbations and should be given for 5 to 7 days. Several studies suggest that corticosteroids accelerate the recovery of FEV1 (forced expiratory volume in 1 second), enhance oxygenation, decrease the duration of hospitalization, and improve clinical outcomes. However, the additional therapeutic benefit regarding FEV1 recovery appears to be most apparent in the first 3 to 5 days. No data are available on the optimum duration of corticosteroid treatment in primary-care patients with acute COPD exacerbations. Given that many COPD patients are treated as outpatients, there is an urgent need to improve the evidence base on COPD management in this setting. The aim of this study is to investigate whether a 3-day treatment with orally administered corticosteroids is non-inferior to a 5-day treatment in acute exacerbations of COPD in a primary-care setting.Methods/designThis study is a prospective double-blind randomized controlled trial conducted in a primary-care setting. It is anticipated that 470 patients with acutely exacerbated COPD will be recruited. Participants are randomized to receive systemic corticosteroid treatment of 40 mg prednisone daily for 5 days (conventional arm, n = 235) or for 3 days followed by 2 days of placebo (experimental arm, n = 235). Antibiotic treatment for 7 days is given to all patients with CRP ≥ 50 mg/l, those with a known diagnosis of bronchiectasis, or those presenting with Anthonisen type I exacerbation. Additional treatment after inclusion is left at the discretion of the treating general practitioner. Follow-up visits are performed on days 3 and 7, followed by telephone interviews on days 30, 90, and 180 after inclusion in the study. The primary endpoint is the time to next exacerbation during the 6-month follow-up period.DiscussionThe study is designed to assess whether a 3-day course of corticosteroid treatment is not inferior to the conventional 5-day treatment course in outpatients with exacerbated COPD regarding time to next exacerbation. Depending on the results, this trial may lead to a reduction in the cumulative corticosteroid dose in COPD patients.Trial registrationClinicalTrials.gov, NCT02386735. Registered on 12 March 2015.

KD025 for Patients with Chronic Graft-Versus-Host Disease (cGVHD) - Long-Term Follow-up of a Phase 2a Study (KD025-208)

KD025 for Patients with Chronic Graft-Versus-Host Disease (cGVHD) - Long-Term Follow-up of a Phase 2a Study (KD025-208)

Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial

Summary Background Type I interferons are involved in systemic lupus erythematosus (SLE) pathogenesis. In a phase 2 trial, anifrolumab, a human monoclonal antibody to type I interferon receptor subunit 1, suppressed interferon gene signatures and substantially reduced SLE disease activity. Here, we sought to confirm the efficacy of anifrolumab versus placebo in a phase 3 trial of adult patients with SLE and moderate-to-severe disease activity despite standard-of-care treatment. Methods TULIP-1 was a double-blind, randomised, controlled, phase 3 trial done at 123 sites in 18 countries. Included patients were aged 18–70 years, with moderate-to-severe SLE, and ongoing stable treatment with either prednisone or equivalent, an antimalarial, azathioprine, mizoribine, mycophenolate mofetil or mycophenolic acid, or methotrexate. Patients were randomly assigned (2:1:2) to receive placebo, anifrolumab 150 mg, or anifrolumab 300 mg intravenously every 4 weeks for 48 weeks. Stable standard-of-care treatment continued except for mandatory attempts at oral corticosteroid tapering for patients receiving prednisone or equivalent of 10 mg/day or more at baseline. The primary outcome was the difference between the proportion of patients who achieved an SLE responder index-4 (SRI-4) response at week 52 with anifrolumab 300 mg versus with placebo. Key secondary outcomes were the difference between the anifrolumab 300 mg group and the placebo group in: proportion of patients in the interferon gene signature test—high subgroup who achieved SRI-4 at week 52; proportion of patients on 10 mg/day or more corticosteroids at baseline who achieved a sustained dose reduction to 7·5 mg/day or less from week 40 to 52; proportion of patients with a cutaneous lupus erythematosus disease area and severity index (CLASI) activity score of 10 or higher at baseline who achieved a 50% or more reduction in CLASI score by week 12; proportion of patients who achieved SRI-4 at week 24; and annualised flare rate through week 52. Other measures of disease activity were also assessed at week 52, including the British Isles Lupus Assessment Group-based composite lupus assessment (BICLA). Safety was also assessed. Efficacy and safety analyses were done in the population of patients who received at least one dose of study drug. This trial was registered at ClinicalTrials.gov (NCT02446912). Findings Between June 9, 2015, and June 16, 2017, 457 patients were randomly assigned to the anifrolumab 300 mg group (n=180), the anifrolumab 150 mg group (n=93), or the placebo group (n=184). The proportion of patients at week 52 with an SRI-4 response was similar between anifrolumab 300 mg (65 [36%] of 180) and placebo (74 [40%] of 184; difference −4·2 [95% CI −14·2 to 5·8], p=0·41). Similarly, proportions of patients with an SRI-4 response at week 24, and at week 52 in patients in the interferon gene signature test—high subgroup, did not differ between the anifrolumab and placebo groups. In patients with baseline oral corticosteroids of at least 10 mg/day, sustained dose reduction to 7·5 mg/day or less was achieved by 42 (41%) of 103 patients in the anifrolumab 300 mg group and 33 (32%) of 102 patients in the placebo group (difference 8·9 [95% CI −4·1 to 21·9]). In patients with CLASI activity score of at least 10 at baseline, at least 50% reduction by week 12 was achieved by 24 (42%) of 58 patients in the anifrolumab 300 mg group and 14 (25%) of 54 in the placebo group (difference 17·0 [95% CI −0·3 to 34·3]). Annualised flare rates were 0·60 for anifrolumab and 0·72 for placebo (rate ratio 0·83 [95% CI 0·60 to 1·14]). BICLA response was achieved by 67 (37%) of 180 patients receiving anifrolumab 300 mg versus 49 (27%) of 184 receiving placebo (difference 10·1 [95% CI 0·6 to 19·7]). Anifrolumab's safety profile was similar to that observed in phase 2, with similar proportions of patients having a serious adverse event between groups (25 [14%] of 180 for anifrolumab 300 mg, ten [11%] of 93 for anifrolumab 150 mg, and 30 [16%] of 184 for placebo). Interpretation The primary endpoint was not reached. However, several secondary endpoints, including reduction in oral corticosteroid dose, CLASI responses, and BICLA responses, suggest clinical benefit of anifrolumab compared with placebo. Conclusive evidence for the efficacy of anifrolumab awaits further phase 3 trial data. Despite the inherent limitations of a 1-year phase 3 study, such as incomplete knowledge of applicability to the general population and scarce detection of rare safety signals, in addition to complications from prespecified restricted medication rules, our results suggest that anifrolumab might have the potential to provide a treatment option for patients who have active SLE while receiving standard therapy. Funding AstraZeneca.

A comprehensive, multidisciplinary, precision medicine approach to discover effective therapy for an undiagnosed, progressive, fibroinflammatory disease

Precision medicine has generated diagnoses for many patients with challenging undiagnosed disorders. Some individuals remain without a diagnosis despite comprehensive testing, and this impedes their treatment. This report addresses the role of personalized medicine in identifying effective therapy for an undiagnosed disease. A 22-year-old woman presented with chronic severe recurrent trismus, facial pain, progressive multicentric inflammatory and fibrotic masses, and high C-reactive protein. Sites of disease included the pterygomaxillary region, masseter muscles, mandible, lung, pericardium, intrabdominal cavity, and retroperitoneum. A diagnosis was not established after an extensive assessment, including multiple biopsies. The patient was subsequently evaluated under the Undiagnosed Diseases Program at the National Institutes of Health. Large scale genotyping, proteomic studies, and in vitro and gene expression analyses of fibroblasts obtained from a major disease locus were performed. Germline genetic testing did not identify strong candidate genes; proteomic studies of the patient's serum and bronchoalveolar lavage fluid and gene expression analyses of her cells were consistent with dysregulation of the tumor necrosis factor-alpha pathway. The patient's cultured fibroblasts were incubated with selected drugs, and cell proliferation was inhibited by hydroxychloroquine. Treatment of the patient with hydroxychloroquine conferred prolonged beneficial clinical effects, including stabilization of trismus and reduction of corticosteroid dose, C-reactive protein, and size of masses. This case represents an example of precision medicine applied to discover effective treatments for individuals with enigmatic undiagnosed disorders.

A multicenter real-world study of bevacizumab in heavily pretreated malignant gliomas: clinical benefit is a plausible end point?

Aim: This multicenter, retrospective study evaluates the clinical benefit (CB) of bevacizumab, alone or in combination, in recurrent gliomas (RG). Patients & methods:The CB was measured as a reduction of corticosteroid dosage and an improvement ≥20 points in the Karnofsky Performance Status lasting ≥3 months. Results: We collected data of 197 RG patients. A CB was observed in 120, patients without significant differences between patients treated with bevacizumab alone or in combination. The rate of patients who achieved a CB and free from progression at 1 year was 21.5 versus 1.4% in patients who did not report CB. Conclusion: The majority of RG patients treated with bevacizumab reported CB. Moreover, patients with CB showed improved survival.

Characterization of inflammatory bowel disease management by vedolizumab and concomitant treatments in real-life clinical practice

Limited data is available on vedolizumab combination therapies in real-world clinical practice. Here, we evaluated the concomitant corticosteroid, immunosuppressive, and 5-aminosalicylic acid utilization of inflammatory bowel disease (IBD) patients treated with vedolizumab in a nationwide, retrospective, non-interventional, multi-centre chart review study. All adult patients from 27 Finnish gastroenterology centres with a diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) who had at least one vedolizumab infusion since it's availability in Finland were included in the study. Data were collected from medical charts at baseline (vedolizumab treatment initiation), week 14, and month 6. The majority of patients who used corticosteroids at the baseline and persisted on vedolizumab treatment for 6 months were taken off corticosteroid treatment by the 6-month time point (CD, 54.5%; UC, 69.8%). Modest corticosteroid dose reductions were observed among treatment persistent CD patients from the baseline until month 6. Corticosteroid users had less vedolizumab discontinuations due to primary ineffectiveness and more discontinuations due to adverse events than patients not using corticosteroids. Vedolizumab may have a corticosteroid sparing effect in real-world clinical practice. Concomitant corticosteroid use may lead to a lower rate of vedolizumab discontinuation due to primary ineffectiveness, but a higher discontinuation rate due to adverse events.

KD025-208: A Phase 2a Study of KD025 for Patients with Chronic Graft Versus Host Disease (cGVHD) - Pharmacodynamics (PD) and Updated Results

Introduction cGVHD is characterized by an imbalance between effector and regulatory arms of the immune system that results in over production of IL-17 and IL-21. A reduction in the regulatory T (Treg) cells limits the ability of the immune system to re-calibrate this pro-inflammatory environment. KD025 is an oral Rho kinase 2 (ROCK2) selective inhibitor. In vitro data demonstrate KD025 modulates immune homeostasis by shifting the Th17/Treg balance towards Treg. Methods 3 cohorts (C1: 200 mg QD, C2: 200 mg BID, and C3: 400 mg QD) of patients (pts) with cGVHD after 1-3 prior lines of systemic therapy were treated in 28-Day cycles until disease progression. The primary endpoint is overall response rate (ORR) (partial/complete response) per 2014 NIH criteria. Additional endpoints include duration of response (DOR), corticosteroid (CS) dose reductions, Lee Symptom Scale (LSS) score and PD. Blood samples were collected at Cycle 1 Day 1 (C1D1), C2D1, C4D1 and C6D25, and shipped at ambient temperature. PBMC were isolated and kept frozen until analysis. Intracellular expression of IL-17A and FOXP3 was determined by flow cytometry. Results Data as of 6-June-2018 for C1 and C2 are included; C3 data will be available 4Q18. 17 and 16 pts were enrolled in C1 and C2 with median age 52 years, time from cGVHD diagnosis to KD025 treatment of 19 months, and 3 prior regimens. Median duration of treatment was37 (C1) and 33 (C2) weeks. KD025 demonstrated ORR of 65% in C1 and 63% in C2. Responses were rapid (76% at first assessment at 8 weeks) and durable (≥20 weeks) in 82% (C1) and 50% (C2) of responders. Median CS dose was reduced 44% (C1) and 26% (C2). 76% and 56% of pts achieved CS dose reductions. 5/33 (15%) pts discontinued CS. 65% (C1) and 50% (C2) achieved a meaningful improvement (≥7 point reduction) in the LSS score. Common AEs were increased LFTs 42%, URI 33%, anemia 27%, nausea 24%, diarrhea 24% and fatigue 21%. Grade 3+ LFT increases were reported for 6 (18%) pts. 2 pts discontinued treatment due to AEs possibly related to KD025 (headache, diarrhea). SAEs were reported for 11/33 pts, none considered related to KD025. There was no apparent increased risk of infection. Exploratory PD analyses revealed an early increase in the percentage of CD4+ Treg cells by C2D1 with a simultaneous decrease in Th17 cells. The percentage of CD4+ Tregs continued to increase, and the Th17 cells continued to decrease through C6D25. Conclusion KD025 achieved responses with little toxicity. Responses are clinically meaningful with durability, reductions in CS doses and improvement in LSS score. PD data indicate KD025 may restore the Th17/Treg balance.

Predictors of Effectiveness of Anakinra in Systemic Juvenile Idiopathic Arthritis.

To seek predictors of therapeutic response to the interleukin (IL)-1 inhibitor anakinra in children with systemic-onset juvenile idiopathic arthritis (sJIA). The clinical charts of all patients with sJIA who were newly treated with anakinra at our center between 2004 and 2017 were reviewed retrospectively. Predictors included baseline demographic, clinical, and laboratory variables as well as previous or concomitant therapies. The effectiveness of anakinra was assessed at 1 year after treatment start. Complete clinical response (CCR) was defined as absence of fever, physician's global assessment ≤ 1, count of active joints ≤ 1, negative C-reactive protein, and ≥ 75% reduction of corticosteroid dose. According to the intention-to-treat principle, patients who had anakinra discontinued before 1 year for any reasons other than disease remission were classified as nonresponders. Statistics included univariate and multivariable analyses. Of the 62 patients included in the study, 24 (39%) met the criteria for CCR at 1 year, whereas 38 (61%) did not. On multivariable analysis, independent correlations with achievement of CCR were identified for shorter disease duration, lower active joint count, higher ferritin level, and greater activity of systemic manifestations. The area under the curve of the model was 0.83. Our findings help to delineate the clinical profile of patients with sJIA who are more likely to benefit from IL-1 blockade. They also underscore the need for studies aimed at examining the therapeutic role of early IL-1 inhibition and to identify biomarkers predicting response to either IL-1 or IL-6 antagonists.

Exclusive abdominal lymphadenopathy as a rare presentation of sarcoidosis

Sarcoidosis is a systemic granulomatous disease. The disease’s immunopathogenic mechanism is the activation of a cell mediated immune response. Lung is the most affected organ, but up to 30% of patients can have extrapulmonary manifestations. Case report: A 21-year-old male presented with a history of nausea, vomiting after meals, epigastric and periumbilical pain for approximately 6 months. Hyporexia and loss of 35 kilograms in 7 months were present, in addition to intermittent low nocturnal fever. His computed tomography (CT) scan (Figure 1) of the abdomen showed the presence of multiple, enlarged mesenteric lymph nodes with homogenous shape, measuring up to 2.0 cm in diameter, extending from the upper abdomen to the pelvis. Histopathologic findings of this lymph nodes showed a sarcoid appearance (Figure 2). Lymphoma, tuberculosis and other infections were excluded through immunohistochemical analysis. Treatment with prednisone was started initially at a dose of 40mg and after 5 weeks the patient were asymptomatic. One year and three months after the onset of treatment, corticosteroid dose reduction was attempted 3 times, with all of them leading to disease relapses. Treatment was optimized with 60mg of prednisone (for 2 weeks) plus 100mg of azathioprine daily. Discussion: The prevalence of gastrointestinal system involvement with clinical manifestations is 0,1 to 0,9%. However, the incidence of subclinical involvement can be higher. Enlarged lymph nodes is present in approximately 30% of cases. Treatment is indicated in sarcoidosis for patients with damage organ function or symptomatic disease and the first-line therapy is corticosteroid.

Effectiveness and safety of omalizumab in severe, persistent IgE-mediated asthma in pediatric and adult patients: a real-world observational study in Egyptian population

Objective: Real-world studies on the effectiveness of omalizumab in Egyptian population with asthma are limited. This study aimed to evaluate the real-world effectiveness and safety of omalizumab as an add-on treatment in pediatric and adult patients with severe, persistent allergic asthma in Egypt. Methods: The primary endpoint of this 16-week, prospective, open-label, multicenter, non-interventional study was the reduction in oral corticosteroid (OCS) dose. Secondary endpoints included reduction in exacerbation, improvements in quality of life and global assessment of omalizumab therapy. Results: Of the 59 patients, 53 completed the study. Add-on omalizumab significantly reduced the proportion of patients receiving OCS at Week 16 versus baseline (81.1% at baseline versus 52.8% at Week 16; p < 0.001). A 55% decrease in the total daily prednisolone-equivalent dose of OCS was observed at the end of the study compared to baseline (p < 0.001). No patients reported exacerbations or missed days from work or school after receiving omalizumab for 16 weeks compared to baseline (both p < 0.001). A statistically significant decrease was observed in asthma control questionnaire-5 scores (p < 0.001). Almost all physicians and patients rated omalizumab therapy as ‘good,’ ‘very good’ or ‘excellent’ in tolerability and effectiveness. No new safety signals were observed in the safety analysis of omalizumab as add-on treatment. Conclusions: Outcomes of this real-world study were consistent with previous effectiveness and safety studies of omalizumab. Omalizumab was effective and well tolerated for the management of severe, persistent IgE-mediated asthma in pediatric and adult patients in Egypt.

Multicentric, Retrospective Study of Extracorporeal Photopheresis, Off-Line System, in Corticosteroid Refractory Acute and Chronic Graft-Versus-Host Disease

BACKGROUNDGraft-versus-host disease (GvHD) remains an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation, despite the improvements in GvHD prophylaxis. First line treatment of GvHD (acute or chronic) consists of high dose corticosteroids, with a response rate of around 50%. Extracorporeal photopheresis (ECP) is an effective and safe treatment strategy in corticosteroid refractory GvHD, although most of the studies are limited to retrospective series. The main objectives of this study were to analyze the clinical response and impact of ECP therapy in corticosteroid dose reduction.METHODS114 patients from 7 Spanish transplantation centers were analyzed retrospectively. The characteristics of the patients are shown on Table 1. A total of 1940 ECP procedures were performed from January-2011 to June-2017 in 65 patients (57%) with acute GvHD (aGvHD) and 49 (43%) with chronic GvHD (cGvHD). Glucksberg and the NIH criteria were used for the diagnosis and grading of acute and chronic GvHD, respectively. All ECP procedures were performed with the off-line system: after the lymphoapheresis, 8-MOP was added to the apheresis product and finally photoinactivated in the Macogenic G1 (Macopharma®) irradiator. During the first 4 weeks, patients underwent 1-2 weekly procedures, followed by 1-2 procedures every 2 weeks and tailored by clinical response. The response was classified as complete response (CR), partial response (PR) or no response (NR). % of the initial corticosteroid dose reduction was registered at the end of treatment.RESULTSPatients with aGvHD underwent a median of 13 processes (interquartile range 9-19), and those with cGvHD a median of 19 processes (IQR 13-24). The median number of processes until response was 3 in patients with aGvHD and 4 for patients with cGvHD. ECP was the second line therapy in the 47% of aGvHD cases and 49% in cGvHD. 71% of the cases of aGvHD were grade 3-4, and 69% of the cases of cGvHD corresponded to severe forms.The overall response rate in aGvHD was 66% (CR 55%), whereas in cGvHD the rate was 67% (CR 22%). The most involved organ was the skin, with a response rate of 80% (CR 68%) in aGvHD and 69% (CR 22%) in cGvHD. In acute digestive GvHD, the response rate was 61% (CR 50%), and 75% (CR 50%) in the chronic form. For liver involvement, response rates were 67% (CR 57%) in acute and 70% (CR 30%) in cGvHD. 80% of the patients with chronic lung involvement showed an overall response (20%CR). At the end of ECP treatment, 71% of the patients treated for aGvHD and 61% of patients with cGvHD were able to reduce the corticosteroid dose, with a median dose reduction of 90% and 100% in all patients, respectively.With a median follow-up of 31 months in aGvHD and 68 months in cGvHD, the 2-year overall survival (OS) was 47% and 83%, respectively. Significant OS differences were noted between responding (CR+PR, 2-year OS 62%) and no responding (NR, 2 year OS 18%, HR=2.5, p<0.001) aGvHD patients. Significant differences were also seen in cGvHD between responding (CR+PR, 2 year OS 93%) and no responding (NR, 2 year OS 62%, HR=3.99, p=0.008) patients.CONCLUSIONSECP is a valid therapeutic alternative in patients with corticosteroid refractory acute and cGvHD, with higher CR rates in patients with aGvHD. ECP allowed for significant corticosteroid dose reductions in more than 2/3 of the patients in both GvHD settings, and granted longer OS in responding patients. The results obtained are similar to those published by other groups. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

KD025-208: A Phase 2a Study of KD025 for Patients with Chronic Graft Versus Host Disease (cGVHD) — Pharmacodynamics and Updated Results

Introduction: cGVHD remains a leading cause of post-transplant morbidity / mortality, exhibiting features of both autoimmune and fibrotic diseases across multiple organ systems.cGVHD is characterized by an imbalance between effector and regulatory arms of the immune system that results in over production of inflammatory cytokines including IL-17 and IL-21. Moreover, a persistent reduction in the number of regulatory T (Treg) cells limits the ability of the immune system to re-calibrate this pro-inflammatory environment.KD025 is an orally available Rho-associated coiled-coil kinase 2 (ROCK2) selective inhibitor. In vitro data have demonstrated that KD025 (1) attenuates IL-21 and IL-17 secretion in human CD4+ T cells via STAT3, IRF4 and RORγt regulation, and (2) leads to increased percentages of Foxp3+ CD4+ T cells via a STAT5-dependent mechanism and upregulates the suppressive function of human Tregs. These MOA suggest that KD025 modulates immune homeostasis by shifting the Th17/Treg balance towards a Treg phenotype. No studies have examined KD025 effects in patients with dysregulation associated with high Th17 and low Tregs.Methods: KD025-208 enrolled 3 cohorts (C1: 200 mg QD, C2: 200 mg BID, and C3: 400 mg QD) of patients (pts) with cGVHD after 1-3 prior lines of systemic therapy. Treatment is in 28-Day cycles until disease progression or unacceptable toxicity. The primary endpoint is the overall response rate (ORR) (% pts achieving partial response (PR) or complete response (CR)) as per 2014 NIH response criteria. Secondary endpoints include duration of response (DOR) and corticosteroid (CS) dose reductions. Exploratory endpoints include Lee Symptom Scale (LSS) score and pharmacodynamics (PD).Peripheral blood samples were collected from all pts at Cycle 1 Day 1 (C1D1), C2D1, C4D1 and C6D25, and shipped at ambient temperature. PBMC were isolated and kept frozen until analysis. The intracellular expression of IL-17A and FOXP3 on viable CD3+ CD4+ cells was determined by using multicolor flow cytometry.Results: Data as of 6-June-2018 for C1 and C2 are included; C3 data will be available 4Q18. 17 and 16 pts were enrolled in C1 and C2 with median age 52 years, median time from cGVHD diagnosis to KD025 treatment of 19 months, and a median of 3 prior treatment regimens. Median duration of treatment was 37 (C1) and 33 (C2) weeks (wks). KD025 demonstrated an ORR of 65% in C1 and 63% in C2. ORR in key subgroups is shown below. Responses were rapid (76% achieved at first assessment at 8 wks) and durable with 82% (C1) and 50% (C2) of responders sustaining response for ≥20 wks.Responses including CRs were observed across all affected organ systems except lung (mouth, eyes, joints/ fascia, skin, upper GI, lower GI, esophagus, liver). A previously reported lung PR was deemed on review to be IPF with no cGVHD involvement.During treatment with KD025, median CS dose was reduced by 44% (C1) and 26% (C2). 76% and 56% of pts achieved CS dose reductions. 5/33 (15%) pts discontinued CS. 65% (C1) and 50% (C2) achieved a meaningful improvement (≥7 point reduction) in the LSS score, including both responders (67%) and non-responders (42%).KD025 has been well tolerated. AEs reported were generally consistent with those expected in pts with advanced cGVHD treated with CS. Common AEs were increased LFTs (42%), URI (33%), anemia (27%), nausea (24%), diarrhea (24%) and fatigue (21%). Increased LFTs did not lead to treatment discontinuation, commonly occurred prior to KD025 dosing and were often considered attributable to cGVHD. Grade 3+ LFT increases were reported for 6 (18%) pts. 2 pts discontinued treatment due to AEs possibly related to KD025 (headache, diarrhea). SAEs were reported for 11/33 (33%) pts, none considered related to KD025 treatment. There was no apparent increased risk of infection.Exploratory PD analyses of PBMCs across C1 and C2 revealed an early increase in the percentage of CD4+ Treg cells by C2D1 of KD025 treatment with a simultaneous decrease in Th17 cells. The percentage of CD4+ Tregs continued to increase, and the Th17 cells continued to decrease through C4D1 and C6D25.Conclusion: Treatment with KD025 has demonstrated encouraging clinical responses in cGVHD pts with little toxicity. Responses have been clinically meaningful as evidenced by durability, reductions in CS doses and improvement in LSS score. Exploratory PD data indicate treatment with KD025 may modulate immune homeostasis by restoring the Th17/Treg balance. DisclosuresJagasia:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Salhotra:Kadmon Corporation, LLC: Consultancy. Bachier:Sanofi: Speakers Bureau; Seattle Genetics: Speakers Bureau. Weisdorf:Seattle Genetics: Consultancy; Pharmacyclics: Consultancy; Equillium: Consultancy; SL Behring: Consultancy; FATE: Consultancy. Green:Kadmon Corporation, LLC: Employment. Schueller:Kadmon Corporation, LLC: Employment. Zanin-Zhorov:Kadmon Corporation, LLC: Employment. Weiss:Kadmon Corporation, LLC: Employment. Eiznhamer:Kadmon Corporation, LLC: Employment. Aggarwal:Kadmon Corporation, LLC: Employment. Blazar:Kadmon Corporation, LLC: Consultancy, Research Funding. Lee:Takeda: Research Funding; Kadmon: Research Funding; Amgen: Consultancy, Research Funding; Mallinckrodt: Honoraria; Incyte: Consultancy; Pfizer: Consultancy; Onyx: Research Funding.

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.

Exclusive abdominal lymphadenopathy as a rare presentation of sarcoidosis

Introduction: Sarcoidosis is a systemic granulomatous disease. The disease’s immunopathogenic mechanism is the activation of a cell mediated immune response. Lung is the most affected organ, but up to 30% of patients can have extrapulmonary manifestations.Case report: A 21-year-old male presented with a history of nausea, vomiting after meals, epigastric and periumbilical pain for approximately 6 months. Hyporexia and loss of 35 kilograms in 7 months were present, in addition to intermittent low nocturnal fever. His computed tomography (CT) scan (Figure 1) of the abdomen showed the presence of multiple, enlarged mesenteric lymph nodes with homogenous shape, measuring up to 2.0 cm in diameter, extending from the upper abdomen to the pelvis. Histopathologic findings of these lymph nodes showed a sarcoid appearance (Figure 2). Lymphoma,tuberculosis and other infections were excluded through immunohistochemical analysis. Treatment with prednisone was started initially at a dose of 40mg a day and after 5 weeks the patient was asymptomatic. One year and three months after the onset of treatment, corticosteroid dose reduction was attempted 3 times, with all of them leading to disease relapses. Treatment was optimized with 60mg of prednisone (for 2 weeks) plus 100mg of azathioprine daily.Discussion: The prevalence of gastrointestinal system involvement with clinical manifestations is 0,1 to 0,9%. However, the incidence of subclinical involvement can be higher. Enlarged lymph nodes are present in approximately 30% of cases. Treatment is indicated in sarcoidosis for patients with damage organ function or symptomatic disease and the first-line therapy is corticosteroids

Corticosteroid use endpoints in neuro-oncology: Response Assessment in Neuro-Oncology Working Group.

Corticosteroids are the mainstay of treatment for peritumor edema but are often associated with significant side effects. Therapies that can reduce corticosteroid use would potentially be of significant benefit to patients. However, currently there are no standardized endpoints evaluating corticosteroid use in neuro-oncology clinical trials. The Response Assessment in Neuro-Oncology (RANO) Working Group has developed consensus recommendations for endpoints evaluating corticosteroid use in clinical trials in both adults and children with brain tumors. Responders are defined as patients with a 50% reduction in total daily corticosteroid dose compared with baseline or reduction of the total daily dose to ≤2 mg of dexamethasone (or equivalent dose of other corticosteroid); baseline dose must be at least 4 mg of dexamethasone daily (or equivalent dose of other corticosteroids) for at least one week. Patients must have stable or improved Neurologic Assessment in Neuro-Oncology (NANO) score or Karnofsky performance status score or Eastern Cooperative Oncology Group (ECOG) (Lansky score for children age <16 y), and an improved score on a relevant clinical outcome assessment tool. These criteria must be sustained for at least 4 weeks after baseline assessment to be considered a response, and are confirmed 4 weeks after that (ie, 8 wk after baseline assessment) to be considered a sustained response. This RANO proposal for corticosteroid use endpoints in neuro-oncology clinical trials may need to be refined and will require prospective validation in clinical studies.

A randomised, multi‐centre phase III study of 3 different doses of intravenous immunoglobulin 10% in patients with chronic inflammatory demyelinating polyradiculoneuropathy (ProCID trial): Study design and protocol

Patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) show varying degrees of response to intravenous immunoglobulin (IVIg) therapy. This randomised phase III study in patients with CIDP (ProCID trial) will compare the efficacy and safety of 3 different doses (0.5, 1.0, and 2.0 g/kg) of IVIg 10% (panzyga) administered every 3 weeks for 24 weeks. The primary efficacy endpoint is the rate of treatment response, defined as a decrease in adjusted inflammatory neuropathy cause and treatment disability score of ≥1 point, in the IVIg 1.0 g/kg arm at week 24. Patients with definite or probable CIDP according to European Federation of Neurological Sciences/Peripheral Nerve Society criteria with IVIg or corticosteroid dependency and active disease are eligible. All potentially eligible patients will undergo IVIg or corticosteroid dose reduction (washout phase) over ≤12 weeks or until deterioration of CIDP (active disease). Patients with deterioration during the washout phase will be randomised to receive study treatment during a dose‐evaluation phase starting with a loading dose of IVIg 2.0 g/kg followed by maintenance treatment with IVIg 0.5, 1.0, or 2.0 g/kg every 3 weeks. Rescue medication (2 doses of IVIg 2.0 g/kg given 3 weeks apart) will be administered to patients in the IVIg 0.5 and 1.0 g/kg groups who deteriorate after week 3 and before week 18 or who do not improve at week 6. Safety, tolerability and quality of life will be assessed. The ProCID study will provide new information on the best maintenance dose of IVIg for patients with CIDP.

Low disease activity—irrespective of serologic status at baseline—associated with reduction of corticosteroid dose and number of flares in patients with systemic lupus erythematosus treated with belimumab: A real-life observational study

BackgroundLow disease activity is a validated target of current systemic lupus erythematosus (SLE) therapy. The aim of this study was to assess the ability of belimumab to achieve low disease activity states in real-life settings. MethodsMulticentre prospective observational study of consecutive SLE patients receiving belimumab for at least 3 months, due to active disease refractory to at least one conventional immunosuppressant. Disease activity, including the recently defined lupus low disease activity state (LLDAS) and remission (clinical SLEDAI-2K = 0), accrual of organ damage, flares and side effects were documented. ResultsNinety-one patients were included [94.5% women, mean (SD) age 45.9 (12.5) years]. Most frequent manifestations were arthritis (76.7%), rash (72.5%), serologic activity (low C3/C4 and/or high anti-dsDNA; 54.9%), hair loss (47.2%) and mucosal ulcers (27.5%). Median (range) duration of treatment was 10.5 (3.0–42.1) months. Belimumab significantly decreased average SLEDAI-2K, physician global assessment (PGA) and daily prednisone dose over time, as early as 3 months after initiation, with over 20% of patients discontinuing corticosteroids. Although reduction in clinical (i.e., excluding serology) SLEDAI-2K was more pronounced in patients who were serologically active (from 8 to 1.5 at 12 months) as compared to serologically inactive (from 6 to 4) at baseline, attainment of LLDAS did not differ between the two groups and was reached by more than 40% of completer patients after 9–12 months. In addition, the number of flares and severe flares was reduced by 62% and 50%, respectively, during the first 12 months of treatment. Twenty patients (22.0%) discontinued treatment due to inadequate response and two due to side effects potentially related to the drug. ConclusionsIn real-life, belimumab is efficacious in achieving low disease activity in over 40% of unselected patients, in combination with reduction of corticosteroid dosage and number of flares. Both serologically active and inactive patients respond to the drug.