Inadequate Symptom Control Research Articles

Safety and efficacy of tofacitinib up to 48 months in patients with active psoriatic arthritis: final analysis of the OPAL Balance long-term extension study.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis. Here we report the final analysis of Oral Psoriatic Arthritis Trial (OPAL) Balance, a 36-month long-term extension study, with a 12-month methotrexate withdrawal substudy, that assessed tofacitinib safety, tolerability, and efficacy in patients with active psoriatic arthritis. For this open-label, long-term extension study, which was run at 124 centres in 16 countries, eligible patients had participated in the OPAL Broaden or OPAL Beyond phase 3 studies. Patients could enter OPAL Balance up to 3 months after completing one of the qualifying studies or discontinuing for reasons other than an adverse event related to study drug. In OPAL Balance, patients received open-label tofacitinib 5 mg twice daily, with increases to 10 mg twice daily for inadequate symptom control allowed from month 1, and reductions to 5 mg twice daily allowed thereafter for safety. Specific conventional synthetic disease-modifying antirheumatic drugs could be continued concomitantly. The primary endpoints were incidence and severity of adverse events, the incidence of laboratory abnormalities, and changes from baseline in laboratory parameters. Participants who were eligible could enter the randomised, double-blind, methotrexate withdrawal substudy (open-label tofacitinib 5 mg twice daily plus either masked placebo or masked methotrexate); safety data from which are included here (up to month 48). Efficacy was reported up to month 36 (substudy data excluded). The risk period for safety outcomes was the time from treatment exposure to the last dose plus 28 days or date of last observation. OPAL Balance is registered with ClinicalTrials.gov (NCT01976364) and is now complete. Between Feb 17, 2014, and March 28, 2016, 686 patients were enrolled and given tofacitinib 5 mg or 10 mg twice daily (179 patients were treated in the substudy and 453 [66%] of 686 completed the long-term extension study or substudy; mean treatment duration 794·6 days [SD 329·2] in long-term extension study, 879·0 days [396·6] in long-term extension study plus substudy). The mean age of participants in the all tofacitinib group was 48·8 years (SD 11·8) and 370 (54%) of 686 participants were female. Up to month 48, 574 (84%) of 686 participants reported all-cause adverse events, 115 (17%) reported serious adverse events, and 78 (11%) discontinued due to an adverse event. Six patients died, one within the risk period (incidence of 0·1 patients with events [95% CI 0·0-0·3] per 100 person-years). The incidences of adverse events of special interest, reported as number of patients with events per 100 person-years, included: 1·7 (1·2-2·5) for herpes zoster (non-serious and serious); 1·0 (0·6-1·6) for serious infections; 0·4 (0·1-0·8) for opportunistic infections; 0·7 (0·4-1·2) for malignancies (excluding non-melanoma skin cancer [NMSC]); 0·9 (0·5-1·5) for NMSC; 0·2 (0·1-0·6) for major adverse cardiovascular events; 0·1 (0·0-0·3) for pulmonary embolism; and 0·4 (0·1-0·8) for arterial thromboembolism. No deep vein thromboses occurred. Laboratory parameter changes were as expected with treatment. Efficacy was sustained up to month 36. This analysis supports the long-term safety (up to 48 months) and efficacy (up to 36 months) of tofacitinib in patients with psoriatic arthritis, which were consistent with previous phase 3 studies. Pfizer.

Characteristics of Advanced Cancer Patients Admitted to the Palliative Care Unit from the Emergency Department.

Aim:People with cancer frequently present to emergency departments (EDs) because of exacerbation of the existing problems and new symptoms, complications of treatments, or difficulties with care and support systems. The aim of the study was to determine the presenting symptoms and demographic characteristics of advanced cancer patients and their caregivers admitted to the palliative care (PC) unit from the ED.Methods:After approval, 139 cancer patients admitted to the ED and referred for PC consultation were included in the study. The medical records of PC unit for all patients and their primary caregivers were retrospectively evaluated. Demographic characteristics, cancer site and metastasis, reasons and frequency for ED admissions, symptoms, duration of hospitalization, and outcomes were recorded. The association between the characteristics of caregivers and emergency visits was also evaluated.Results:Among all patients, 61.9% were >60 years old, 58.3% were male, and 71.2% were married. The most frequent site of cancer was gastrointestinal system (39.6%), lungs (18.7%), and genitourinary system (12.2%). The reasons for emergency visits were found as inadequate symptom control (65.5%), dying patient (30.2%), lack of psychosocial support (3.6%), and symptom of other comorbidities (0.7%). The most frequent symptoms were feeling of not well-being, tiredness, and lack of appetite. There was no difference in the number of admissions according to caregivers. Ninety-seven patients (69.8%) died at the PC unit and 42 (30.2%) were discharged.Conclusion:PC system needs to be integrated into all health-care disciplines including EDs. While improving a community- and home-based PC, education of patients, caregivers, and health professionals must also be provided.

Pharmacotherapy of allergic rhinitis: position of a clinical pharmacologist

Pharmacotherapy for allergic rhinitis is based on different categories of drugs used either in monotherapy or in combination regimens. The current clinical guidelines suggest a stepwise approach to pharmacotherapy for allergic rhinitis. The use of intranasal corticosteroids is considered as the preferred second-stage pharmacotherapy. Inadequate control of AR symptoms in first-line therapy is a common problem. Integrated care pathways (ICP), developed taking into account the data obtained about patients using a mobile application, suggest the use of intranasal corticosteroids as the first line of therapy, including in patients with intermittent rhinitis who have not previously received treatment when assessing the condition according to the VAS for more than 5 points, in patients who received earlier treatment when assessing the condition according to the VAS less than 5 points. According to the data in the medical decision support system and continuing medical education UpToDate, inhaled corticosteroids are considered as the first-line drugs for the pharmacotherapy of allergic rhinitis. In terms of pharmacodynamic efficacy, intranasal corticosteroids are comparable to each other. The selection criteria can be considered: the value of systemic absorption; lipophilicity; the start time of the action; frequency of introduction, organoleptic properties; the possibility of influencing non-nasal symptoms. The use of sprays containing both a glucocorticoid and an antihistamine (mometasone furoate/azelastine hydrochloride) opens up additional pharmacotherapeutic possibilities in the treatment of allergic rhinitis.

Surgical Treatment of Severe Bowel Obstruction as a Rare Complication Following Allogenic Hematopoietic Stem Cell Transplantation

Gastrointestinal graft-versus-host disease (GVHD) and cytomegalovirus (CMV) disease are common complications occurring after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and contribute to a high degree of morbidity and mortality associated with allo-HSCT. Herein, we present a patient with severe intestinal GVHD complicated by recurring CMV enteritis, which overall resulted in severe terminal ileum stenosis. The patient underwent laparoscopic ileocecal resection that significantly reduced symptoms and possibly prevented the development of fulminant ileus. Surgical treatment is rarely used in the treatment of gastrointestinal GVHD; however, the current patient history illustrates that patients with inadequate symptom control and severe inflammatory bowel stenosis can be successfully managed with surgery. We also review published case reports on surgical treatment for severe gastrointestinal GVHD.

Patient Reported Outcomes Among Systemic Mastocytosis (SM) Patients in Routine Clinical Practice: Results from the TouchStone Survey

Introduction: SM is a rare, clonal mast cell neoplasm characterized by uncontrolled proliferation and activation of mast cells driven by the KIT D816V mutation, which leads to severe and unpredictable symptoms. This study evaluated disease and healthcare system burden of SM in a real-world treatment setting in the US. Methods: In this cross-sectional study, SM patients recruited through the Mast Cell Connect Registry completed an online survey. The 100-item survey consists of symptom assessments using the ISM-SAF© and widely used patient-reported outcomes (PRO) measures including the Short Form (SF)-12, Work Productivity and Activity Impairment (WPAI), and questions regarding SM-related medication and physician and emergency department (ED) visits during the past year. Patients ≥18 years with a self-reported diagnosis were included after providing informed consent. Established PRO measures were scored using established scoring algorithms. Data from the first 30 patients enrolled were analyzed using descriptive statistics. Results: Thirty patients completed the survey: 87% female; mean age of 54 years; mean time since diagnosis of 8 years; mean time from symptom onset to diagnosis of 7 years; 80% reported indolent SM, 10% reported aggressive SM, 3% reported smoldering SM, and the remainder (7%) were uncertain of their type. Ninety percent reported ≥10 symptoms during the past year, the most bothersome being abdominal/stomach pain (17%), anaphylactic episodes (13%), diarrhea/loose stools (13%), and fatigue (10%). Most patients indicated they have moderate (43%) or severe (33%) disease. Symptom Burden and Quality of Life (QoL) Impact Mean ± SD mental and physical component summary scores from the SF-12 were 44 ± 1.8 and 43 ± 2.5, respectively, indicating below average health and mental well-being. The mean total symptom score (TSS) from the ISM-SAF was 50, with >28 indicating moderate-severe SM. Nearly all (27/30) patients reported that they strongly agreed (27%), agreed (40%) or somewhat agreed (23%) that SM had a negative impact on their QoL, and 50% (15/30) reported feeling a great deal (17%), quite a bit (10%), or somewhat (23%) depressed or discouraged due to their disease. Use of Healthcare Services & Medications Patients reported encounters with multiple physicians over the course of 1 year (Table). Most patients (90%) reported taking ≥2 over-the-counter (OTC) medications, and 40% of patients reported taking >3 prescription medications to manage SM. Twenty percent of survey respondents visited the ED due to anaphylaxis, with 50% of these patients requiring ED care for anaphylaxis on 3 different occasions. Fifty-seven percent (17/30) of patients reported managing at least 1 anaphylactic episode at home without visiting the ED, with 4 of these patients reporting ≥12 anaphylactic episodes within the past year. Work Impairment Limited activities due to pain attributed to SM were reported by 60% (18/30) of patients, and 56% (17/30) of patients indicated that pain interfered with their ability to work. 17% of respondents reported they were unable to work for pay, 46% of patients reported having to reduce work hours because of SM, and 20% of patients had filed for disability, all due to SM. Conclusions: Despite close management by healthcare providers, and taking prescription and OTC medications, early findings from the TouchStone survey show that the majority of SM patients continue to report significant burden of disease, including inadequate symptom control, negative effects on QoL, reduced ability to work, frequent physician visits to manage SM and multiple, potentially costly, ED visits. These findings suggest high unmet medical need underscoring the value of more effective therapeutic interventions. Disclosures Mesa: LaJolla Pharma: Consultancy; Novartis: Consultancy; Sierra Onc: Consultancy; Abbvie: Research Funding; Celgene: Research Funding; CTI: Research Funding; Genetech: Research Funding; Incyte: Research Funding; Promedior: Research Funding; Samus: Research Funding. Sullivan:Blueprint Medicines Corporation: Current Employment, Current equity holder in publicly-traded company. Dubinsky:Blueprint Medicines Corporation: Current Employment, Current equity holder in publicly-traded company. Carroll:Blueprint Medicines Corporation: Consultancy, Current equity holder in publicly-traded company. Mathias:Blueprint Medicines Corporation: Other: employed by Health Outcomes Solutions, which received funding Blueprint for providing assistance in developing the Touchstone survey. Castells:Annals of Allergy, Asthma & Immunology: Other: Editorial Board; UpToDate: Other: Author fee; Blueprint Medicines Corporation: Consultancy, Other: Clinical trials: Principle Investigator.

Impact of allergic rhinitis on the day-to-day lives of children: insights from an Australian cross-sectional study

Study design and objectiveCross-sectional, observational survey to describe the impact of allergic rhinitis (AR) on Australian children (2 to 15 years).MethodsParticipants (n=1541), parents of children aged 2 to 15 years,...

S1361 Healthcare Resource Use and Associated Costs in the Three Years Following the Initial Diagnosis of Diabetic or Idiopathic Gastroparesis: A Retrospective Claims Analysis

INTRODUCTION: Diabetic gastroparesis (DG) and idiopathic gastroparesis (IG) are the two most common forms of gastroparesis (GP). Because of the limited treatment options, many patients (pts) have inadequate symptom control which may lead to increased healthcare resource use (HRU). This study aimed to quantify the economic burden in HRU and associated costs of DG/IG in the United States over the 3 years (yrs) after first GP diagnosis (dx). METHODS: Adults newly diagnosed with DG or IG were identified in Optum’s de-identified Clinformatics® Data Mart Database (Q1-2007 to Q1-2019). Pts were continuously enrolled for ≥1 yr before and ≥1 yr after their first GP dx (index date). For controls without GP dx, index dates were randomly selected. Pts with DG/IG were matched 1:1 to controls using a mixed approach of exact matching (i.e., age, sex, complete yrs of follow-up post-index) and propensity score matching (i.e., income, education, index yr, Charlson Comorbidity Index [CCI] comorbidities, diabetic complications [DG only]). All-cause HRU and direct healthcare costs per person-year (PPY) were compared between DG/IG cases and matched controls in the 3 yrs post index date. RESULTS: DG and IG cohorts included 18,015 and 14,305 pts (mean age: 62 and 54 yrs; 34% and 24% males), respectively. DG/IG pts had a high comorbidity burden at baseline (DG: 34% chronic pulmonary disease, 29% renal disease; IG: 28% chronic pulmonary disease). Demographics and CCI comorbidities were balanced between GP pts and controls (Table 1). DG/IG pts had significantly higher annual HRU compared to matched controls in the first 3 yrs post-index, with the highest gap observed in Yr 1 (Figure 1). Healthcare costs were also significantly higher for DG/IG pts vs. controls across all 3 yrs post-index (mean total cost differences PPY: DG Yr 1 $34,885, Yr 2 $28,071, Yr 3 $25,606; IG Yr 1 $23,176, Yr 2 $16,627, Yr 3 $14,396; see Figure 2 for Yr 1 cost breakdown by service setting). Patterns of disease burden did not change in a sensitivity analysis with additional adjustment for conditions associated with GP (e.g., anemia, anxiety disorder). CONCLUSION: This study showed a substantial economic burden of both DG and IG among adults, highest in the first yr after dx and persistent over 3 yrs. In the first yr after dx, DG and IG pts had healthcare costs approximately two-fold higher than for the matched controls, emphasizing the need for more effective treatments that may reduce the burden of illness.Table 1Figure 1Figure 2

Effectiveness of mepolizumab therapy in patients with severe eosinophilic asthma: Austrian real-life data

BackgroundMepolizumab was effective in several randomized clinical trials (RCTs) in patients with severe eosinophilic asthma, but evidence for symptom control in a real-world population is scarce. ObjectiveTo assess asthma symptom control, lung function, use of oral corticosteroids, and biomarkers after mepolizumab initiation in real-world clinical practice. MethodsThirty-five adult patients with severe eosinophilic asthma and inadequate asthma symptom control, including former smokers and patients with cardiac disease, were enrolled in a prospective single-arm real-world study. Asthma control tests (ACT), exacerbations, spirometry (pre-bronchodilator forced expiratory volume in 1 s [FEV1]), and oral corticosteroid doses were documented. Further assessments included peripheral blood eosinophil counts and adverse events. ResultsAfter mepolizumab initiation asthma symptom control was significantly improved with the median ACT score of 12.5 at baseline (interquartile range [IQR ]10.5–19.5) rising to 19 (15–22.5) after 4 weeks. The improvement was maintained throughout the observation period of 20 weeks. Likewise, exacerbations were reduced. After 8 weeks of mepolizumab daily OCS doses were reduced from 6.25 mg daily (0–20) at baseline to 2.5 mg daily (0–11.9) at week 8 (P < 0.001). FEV1 remained generally unchanged during the course of the study. Eosinophil counts rapidly declined and remained at a low level during the observation period. No new safety signals were observed in this study. ConclusionMepolizumab improved asthma symptom control and had a steroid-sparing effect. Efficacy in this real-world study was comparable to RCTs, despite a history of smoking and comorbidities in many of the patients included.

Neonatal End-of-Life Symptom Management

Purpose of review: Despite advances in technology and treatment options, over 15,000 neonates die each year in the United States. The majority of the deaths, with some estimates as high as 80%, are the result of a planned redirection of care or comfort measures only approach to care. When curative or life-prolonging interventions are not available or have been exhausted, parents focus on preserving quality of life and eliminating needless suffering. Parents hope their child will have a peaceful death and will not feel pain. A significant component of end-of-life care is high quality symptom evaluation and management. It is important that neonatal providers are knowledgeable in symptom management to address common sources of suffering and distress for babies and their families at the end-of-life (EOL).Recent findings: Medically complex neonates with life-threatening conditions are a unique patient population and there is little research on end-of-life symptom assessment and management. While there are tools available to assess symptoms for adolescents and adults, there is not a recognized set of tools for the neonatal population. Nonetheless, it is widely accepted that neonates experience significant symptoms at end-of-life. Most commonly acknowledged manifestations are pain, dyspnea, agitation, and secretions. In the absence of data and established guidelines, there is variability in their clinical management. This contributes to provider discomfort and inadequate symptom control.Summary: End-of-life symptom assessment and management is an important component of neonatal end-of-life care. While there remains a paucity of studies and data, it is prudent that providers adequately manage symptoms. Likewise, it is important that providers are educated so that they can effectively guide families through the dying process by discussing disease progression, physical changes, and providing empathetic support. In this review, the authors make recommendations for non-pharmacological and pharmacological management of end-of-life symptoms in neonates.

Bronchoalveolar lavage cytokine patterns in children with severe neutrophilic and paucigranulocytic asthma

Asthma is a complex heterogeneous disease occurring in adults and children that is characterized by distinct inflammatory patterns. While numerous studies have been performed in adults, little is known regarding the heterogeneity of severe asthma in children, particularly inflammatory signatures involving the air spaces. We sought to determine the relationship of bronchoalveolar lavage (BAL) cytokine/chemokine expression patterns in children with severe therapy-resistant asthma stratified according to neutrophilic versus nonneutrophilic BAL inflammatory cell patterns. Children with severe asthma with inadequate symptom control despite therapy underwent diagnostic bronchoscopy and BAL. Inflammatory cytokine/chemokine concentrations were determined using a multiplex protein bead assay. Analysis of BAL constituents with an unbiased clustering approach revealed distinct cytokine/chemokine patterns, and these aligned with pathways associated with type 2 innate lymphoid cells, monocytes, neutrophil trafficking, and T effector cells. All cytokines examined (n= 27) with 1 exception (vascular endothelial growth factor) were overexpressed with BAL neutrophilia compared with nonneutrophilic asthma, and this was confirmed in a cross-validation analysis. Cytokines specifically responsible for Th17 (IL-17, IL-6, G-CSF) and Th1 differentiation and expression (IL-12, TNF-α, IFN-γ) were enhanced in the neutrophilic cohorts. Neutrophilic groups were also characterized by higher prevalence of bacterial and viral pathogens; however, cytokine expression patterns manifested independently of pathogen expression. The results demonstrate that children with refractory asthma and neutrophilic inflammation had a BAL cytokine pattern consistent with a mixed Th17/Th1/Th2 response. In contrast, nonneutrophilic asthma presented independently of cytokine overexpression.

Pragmatic cluster randomized trial to evaluate effectiveness and implementation of enhanced EHR-facilitated cancer symptom control (E2C2)

BackgroundThe prevalence of inadequate symptom control among cancer patients is quite high despite the availability of definitive care guidelines and accurate and efficient assessment tools.MethodsWe will conduct a hybrid type 2 stepped wedge pragmatic cluster randomized clinical trial to evaluate a guideline-informed enhanced, electronic health record (EHR)-facilitated cancer symptom control (E2C2) care model. Teams of clinicians at five hospitals that care for patients with various cancers will be randomly assigned in steps to the E2C2 intervention. The E2C2 intervention will have two levels of care: level 1 will offer low-touch, automated self-management support for patients reporting moderate sleep disturbance, pain, anxiety, depression, and energy deficit symptoms or limitations in physical function (or both). Level 2 will offer nurse-managed collaborative care for patients reporting more intense (severe) symptoms or functional limitations (or both). By surveying and interviewing clinical staff, we will also evaluate whether the use of a multifaceted, evidence-based implementation strategy to support adoption and use of the E2C2 technologies improves patient and clinical outcomes. Finally, we will conduct a mixed methods evaluation to identify disparities in the adoption and implementation of the E2C2 intervention among elderly and rural-dwelling patients with cancer.DiscussionThe E2C2 intervention offers a pragmatic, scalable approach to delivering guideline-based symptom and function management for cancer patients. Since discrete EHR-imbedded algorithms drive defining aspects of the intervention, the approach can be efficiently disseminated and updated by specifying and modifying these centralized EHR algorithms.Trial registrationClinicalTrials.gov, NCT03892967. Registered on 25 March 2019.

Feedback control for deep brain stimulation for motor disorders

Deep brain stimulation (DBS) is an effective treatment for many people living with Parkinson’s disease (PD). Although the primary treatment for PD is based on medications, disease progression eventually leads to inadequate symptom control. DBS provides benefits by alleviating motor dysfunctions such as muscle rigidity and tremor. DBS devices deliver electric pulse trains into specific brain regions via implanted electrodes. Existing DBS systems usually provide continuous stimulation with constant settings of parameters such as the amount of charge delivered per pulse. However, PD is characterised by fluctuations in the severity and frequency of impairments. DBS would be improved if stimulation settings were adjusted automatically in response to each patient’s ever-changing needs. This requires a device incorporating sensing of signals that estimate the severity of motor impairment linked to an adaptive control algorithm that optimises therapeutic stimulation. Several types of signals are candidates for this function. Spontaneous local field potentials recorded by the DBS electrodes have shown promise in some experimental studies of adaptive DBS. More recently, DBS-evoked potentials have been reported. In particular, evoked resonant neural activity has properties including a larger amplitude than spontaneous potentials, suggesting it may be a suitable feedback signal to control adaptive DBS.

A6 EFFECTS OF ELUXADOLINE TREATMENT ON ABDOMINAL AND BOWEL SYMPTOMS IN PATIENTS WITH IRRITABLE BOWEL SYNDROME WITH DIARRHEA REPORTING INADEQUATE SYMPTOM CONTROL WITH LOPERAMIDE: AGGREGATED RESULTS FROM PHASE 3 AND 4 CLINICAL TRIALS

Abstract Background The heterogeneous nature of irritable bowel syndrome with diarrhea (IBS-D) presents a complex challenge in the management of a wide range of symptoms. Despite the need for more effective treatments that provide global IBS-D symptom relief, many therapies currently available in Canada only treat individual IBS-D symptoms. Eluxadoline (ELX) is a mixed µ- and κ-opioid receptor agonist and δ-opioid receptor antagonist approved by Health Canada for the treatment of IBS-D in adults. Aims To analyze the efficacy of ELX for managing a constellation of IBS-D symptoms among patients (pts) self-reporting inadequate responses to loperamide (LOP) from Phase 3 and 4 trials of ELX. Methods Adults with IBS-D were randomized to placebo (PBO) or ELX (75 or 100 mg) twice daily (BID) for 26 or 52 weeks in two Phase 3 trials (NCT01553591 and NCT01553747); the data from a subset reporting inadequate IBS-D symptom control with prior LOP use were pooled and prospectively analyzed. In the Phase 4 trial (RELIEF: NCT02959983), IBS-D pts with self-reported inadequate symptom control with LOP over the previous 12 months were randomized to PBO or ELX 100 mg BID for 12 weeks. In all trials, pts recorded their daily IBS-D symptoms including worst abdominal pain (0–10 scale), stool consistency (Bristol Stool Form Scale score 1–7), and daily urgency episodes. Results for ELX 100 mg vs. PBO were evaluated after 12 weeks of treatment, which included the generation of radar plots to visualize multiple efficacy endpoints. Results Of pts enrolled in the Phase 3 trials with prior LOP use, inadequate control of IBS-D symptoms was reported in 58.9% (n=166) and 58.8% (n=174) of pts in the PBO and ELX groups, respectively; in the Phase 4 trial, 174 and 172 pts were treated with PBO and ELX, respectively. ELX-treated pts had a greater proportion of responders compared to PBO-treated pts for all outcomes, including a significant increase in the proportion of pts achieving both ≥50% and ≥75% urgency-free days in the Phase 3 trials (Figure). Analysis of the global symptoms of pts enrolled in the Phase 4 trial further supported these results. Across Phase 3 and 4 trials, adverse events occurred in similar proportions regardless of treatment, with the most common being nausea. Conclusions In pts with inadequate responses to LOP, a greater proportion of ELX-treated pts were responders compared to PBO-treated pts in all Phase 3 and 4 trials for the respective primary composite endpoints, abdominal pain, stool consistency, and urgency after 12 weeks of treatment. These results validate the effectiveness of ELX in alleviating IBS-D symptoms in this population. Funding Agencies Writing assistance by Complete HealthVizion, funded by Allergan plc

Longitudinal follow-up with VIM thalamic deep brain stimulation for dystonic or essential tremor.

To assess longitudinal tremor outcomes with ventral intermediate nucleus deep brain stimulation (VIM DBS) in patients with dystonic tremor (DT) and to compare with DBS outcomes in essential tremor (ET). We retrospectively investigated VIM DBS outcomes for 163 patients followed at our center diagnosed with either DT or ET. The Fahn-Tolosa-Marin tremor rating scale (TRS) was used to assess change in tremor and activities of daily living (ADL) at 6 months, 1 year, 2-3 years, 4-5 years, and ≥6 years after surgery. Twenty-six patients with DT and 97 patients with ET were analyzed. Compared to preoperative baseline, there were significant improvements in TRS motor up to 4-5 years (52.2%; p = 0.032) but this did not reach statistical significance at ≥6 years (46.0%, p = 0.063) in DT, which was comparable to the outcomes in ET. While the improvements in the upper extremity tremor, head tremor, and axial tremor were also comparable between DT and ET throughout the follow-up, the ADL improvements in DT were lost at 2-3 years follow-up. Overall, tremor control with VIM DBS in DT and ET was comparable and remained sustained at long term likely related to intervention at the final common node in the pathologic tremor network. However, the long-term ADL improvements in DT were not sustained, possibly due to inadequate control of concomitant dystonia symptoms. These findings from a large cohort of DT indicate that VIM targeting is reasonable if the tremor is considerably more disabling than the dystonic features. This study provides Class IV evidence that VIM DBS improves tremor in patients with DT or ET.

Inhaled levodopa for intermittent treatment of OFF episodes in patients with Parkinson’s disease

ABSTRACTIntroduction: Many patients with advanced Parkinson’s disease (PD) have inadequate control of motor symptoms despite optimized treatment. Predictable and unpredictable OFF periods severely interfere with the quality of life. A drug that easily and rapidly reverts the OFF state is still needed. Subcutaneous apomorphine, the only approved drug for this indication, although efficacious, is not widely used probably due to its potential side effects and complicated administration.Levodopa is the most efficacious drug for the treatment of PD motor symptoms. However, issues related to the oral route and intestinal absorption in later disease stages render this route lengthy and inefficacious.Areas covered: Literature on the development of an inhaled formulation of levodopa has been reviewed. Significant advances in the field of pulmonary delivery systems and in dry powders have enabled the development of a new formulation of levodopa that can be inhaled and adequate blood levels rapidly achieved, bypassing intestinal absorption. Several clinical trials have reported efficacy, safety, and tolerability data. Some pulmonary-related adverse events have been reported but are mostly mild.Expert opinion: This new way of administering levodopa is likely to be very welcome and may fill a gap for OFF rescue treatments, at least for some patients.

Allergen immunotherapy: definition, indications, and reactions.

Specific allergen immunotherapy is the administration of increasing amounts of specific allergens to which the patient has type I immediate hypersensitivity. It is a disease-modifying therapy, indicated for the treatment of allergic rhinitis, allergic conjunctivitis, allergic asthma, and Hymenoptera hypersensitivity. Specific immunoglobulin E (IgE) antibodies for appropriate allergens for immunotherapy must be documented. Indications for allergen immunotherapy include (1) inadequate symptom control despite pharmacotherapy and avoidance measures; (2) a desire to reduce the morbidity from allergic rhinitis and/or asthma, or reduce the risk of anaphylaxis from a future insect sting; (3) when the patient experiences undesirable adverse effects from pharmacotherapy; and (4) when avoidance is not possible. Several studies reported that immunotherapy in allergic rhinitis seems to prevent the development of new allergic sensitizations and/or new onset asthma. Humoral-, cellular-, and tissue-level changes occur with allergen immunotherapy, including induction of allergen-specific regulatory T and B cells, interleukin 10, and transforming growth factor β production; suppression of T-helper type 2 cell proliferation; large increases in anti-allergen IgG4 antibodies; and reduction in basophil, mast cell, and eosinophil mediator release. Allergen immunotherapy can be administered either subcutaneously in the physician's office or sublingually by the patient at home. The use of immunotherapy in food allergy is still under investigation.

468 Effects of Eluxadoline on a Range of Bowel and Abdominal Symptoms in Patients With Irritable Bowel Syndrome With Diarrhea who Report Inadequate Symptom Control With Loperamide

INTRODUCTION: The efficacy and safety of eluxadoline (ELX), a US Food and Drug Administration-approved mixed μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist for treating adult patients with irritable bowel syndrome with diarrhea (IBS-D), were evaluated in patients who self-reported inadequate response to loperamide in the RELIEF trial. Radar plots were generated from these results to interpret improvements across a spectrum of efficacy measures in ELX-treated patients. METHODS: A Phase 4, multicenter, placebo (PBO)-controlled, double-blind study randomized patients with IBS-D (Rome III criteria) with intact gallbladders who reported overall inadequate IBS symptom control with loperamide in the preceding 12 months to oral ELX (100 mg twice daily) or PBO for 12 weeks (RELIEF; NCT02959983). Patients rated IBS symptoms including worst abdominal pain (WAP), abdominal bloating, abdominal discomfort, stool consistency, number of bowel movements (BMs), and urgency episodes daily. Adequate relief of IBS symptoms was assessed weekly. Response rates over Weeks 1–12 and change from baseline to Week 12 were graphed using radar plots for the following endpoints: primary efficacy composite response (simultaneous daily improvement of ≥40% in WAP score vs. baseline and Bristol Stool Form Scale score &lt;5 [or no BM] on ≥50% of treatment days); stool consistency response as per the primary endpoint; urgency-free response calculated using criteria of ≥50% or ≥75% of days with no urgency episodes; adequate relief response defined as a weekly “yes” response for ≥50% of treatment weeks; WAP response calculated using criteria of ≥30%, ≥40%, or ≥50% improvement vs. baseline. RESULTS: In this study cohort, baseline symptom scores were similar between the treatment groups (Table 1). Significantly higher proportions of ELX-treated patients were composite, stool consistency, and ≥30%, ≥40%, and ≥50% WAP responders vs. PBO at Week 12 (Figure 1). A greater proportion of ELX- vs. PBO-treated patients were also urgency-free and adequate relief responders. ELX-treated patients experienced greater improvements from baseline in WAP, abdominal bloating and discomfort, BM frequency, and urgency episodes vs. PBO (Figure 2). CONCLUSION: Across 13 endpoints, ELX treatment led to improvements vs. PBO, indicating efficacy across a multitude of IBS-D symptoms among patients with prior inadequate symptom control with loperamide.

MANAGE-PD: A clinician-reported tool to identify patients with Parkinson's disease inadequately controlled on oral medications – results from vignette-based validation

To evaluate the reliability and validity of MANAGE-PD tool. Timely identification of advancing symptoms of people living with Parkinson’s Disease for clinical practice improvement. MANAGE-PD is a simple clinician-reported screening tool developed to address this practice gap. Through timely evaluation of PD symptoms. Hypothetical vignettes (n = 10) were developed to represent a wide spectrum of disease severity. this tool was conducted via a web-based survey of selected panelists. Steering Committee classified each vignette into 3 categories: adequately controlled on oral therapy; inadequately controlled on oral therapy and recommend oral optimization only; inadequately controlled on oral therapy and recommend evaluation for device-aided therapies along with oral optimization. Each panelist evaluated one anchor vignette and four randomly assigned vignettes using the MANAGE-PD tool. Concordance between clinical judgment for management of patient versus MANAGE-PD recommendation was assessed. The panel included MDS (n = 19) from 15 countries, with extensive experience in treating PD [Mean: 24.4 ± 7.6 years; Mean patients treated/month: 73.2 ± 45.4]. In open-ended feedback, panelists reported no issues with usage of the tool. The determination of inadequate symptom control and possible eligibility of device-aided therapies was made based on frequency and severity of motor symptoms, non-motor symptoms and functional limitations. A high concordance between clinical judgement and MANAGE-PD recommendation was observed (Intra-class co-efficient: 0.82; weighted kappa statistic:0.71; unweighted kappa statistic:0.78; concordance for the categories ranged from 82.35 to 88.24%). MANAGE-PD demonstrated high reliability and validity. Future steps include validation with a large global survey of general neurologists and optimizing scoring algorithm based on patient-level data.

442 – Safety Profile of Eluxadoline in Patients with Irritable Bowel Syndrome with Diarrhea Reporting Inadequate Symptom Control with Prior Loperamide Use: A Phase 4 Study (Relief)

442 – Safety Profile of Eluxadoline in Patients with Irritable Bowel Syndrome with Diarrhea Reporting Inadequate Symptom Control with Prior Loperamide Use: A Phase 4 Study (Relief)

440 – Robustness of Eluxadoline for the Treatment of Irritable Bowel Syndrome with Diarrhea in Patients Who Report Inadequate Symptom Control with Prior Loperamide Use: A Phase 4 Study (Relief)

440 – Robustness of Eluxadoline for the Treatment of Irritable Bowel Syndrome with Diarrhea in Patients Who Report Inadequate Symptom Control with Prior Loperamide Use: A Phase 4 Study (Relief)