Relapsing Forms Research Articles

Nursing Management of Gastrointestinal Adverse Events Associated With Delayed-Release Dimethyl Fumarate: A Global Delphi Approach

Gastrointestinal (GI) adverse events (AEs) are commonly encountered with delayed-release dimethyl fumarate (DMF), an approved treatment for relapsing multiple sclerosis (MS). Two hundred thirty-nine MS nurses from 7 countries were asked to complete a 2-round Delphi survey developed by a 7-member steering committee. Questions pertained to approaches for mitigating DMF-associated GI AEs. Ninety-six percent of nurses followed the label recommendation for DMF dose titration in round 1, but 77% titrated the DMF dose more slowly than recommended in round 2. Although 86% of nurses advised persons with relapsing forms of MS (PWMS) to take DMF with food, patients were not routinely informed of appropriate types of food to take with DMF. Most nurses recommended both pharmacologic and nonpharmacologic symptomatic therapies for PWMS who experienced GI AEs on DMF. Pharmacologic and nonpharmacologic symptomatic therapies were regarded as equally effective at keeping PWMS on DMF. In round 2, 58% of nurses stated that less than 10% of PWMS who temporarily discontinued DMF went on to permanently discontinue treatment. Sixty-six percent of nurses stated that less than 10% of PWMS permanently discontinued DMF because of GI AEs in the first 6 months of treatment in round 1. Most nurses agreed that patient education on potential DMF-associated GI AEs contributes to adherence. This first real-world nurse-focused assessment of approaches to caring for PWMS with DMF-associated GI AEs suggests that, with implementation of slow dose titration, symptomatic therapies, and educational consultations, most PWMS can remain on DMF and, when necessary after temporary discontinuation, successfully restart DMF.

Expression of p53 N-terminal isoforms in B-cell precursor acute lymphoblastic leukemia and its correlation with clinicopathological profiles

BackgroundTP53 mutations occur in only about 3% of primary and 10–20% of relapse B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). However, alternative mechanisms may contribute to functionally impairing the p53 pathway in the absence of a mutation. Candidate mechanisms include overexpression of p53 mRNA variants encoding either dominant-negative p53 protein isoforms such as Delta40p53 and Delta133p53, or modulatory isoforms such as p53beta, which counteract the effects of Delta133p53 on replicative senescence in T-lymphocytes.MethodsWe used semi-quantitative reverse-transcriptase PCR (RT-PCR) and Western blot to investigate the expression of full length p53 (TAp53), Delta40p53, Delta133p53 or p53beta in diagnostic marrow from a clinical cohort of 50 BCP-ALL patients without TP53 mutation (29 males and 21 females, age range 2–14 years) and in the bone marrow cells of 4 healthy donors (used as controls).ResultsIrrespective of isoforms, levels of p53 mRNA were low in controls but were increased by 2 to 20-fold in primary or relapse BCP-ALL. TAp53 was increased in primary BCP-ALL, Delta40p53 was elevated in relapse BCP-ALL, whereas Delta133p53 and p53beta were increased in both. Next, mRNA levels were used as a basis to infer the ratio between protein isoform levels. This inference suggested that, in primary BCP-ALL, p53 was predominantly in active oligomeric conformations dominated by TAp53. In contrast, p53 mostly existed in inactive quaternary conformations containing ≥2 Delta40 or Delta133p53 in relapse BCP-ALL. Western blot analysis of blasts from BCP-ALL showed a complex pattern of N-terminally truncated p53 isoforms, whereas TAp53beta was detected as a major isoform. The hypothesis that p53 is in an active form in primary B-ALL was consistent with elevated level of p53 target genes CDKN1A and MDM2 in primary cases, whereas in relapse BCP-ALL, only CDKN1A was increased as compared to controls.ConclusionExpression of p53 isoforms is deregulated in BCP-ALL in the absence of TP53 mutation, with increased expression of alternative isoforms in relapse BCP-ALL. Variations in isoform expression may contribute to functional deregulation of the p53 pathway in BCP-ALL, specifically contributing to its down-regulation in relapse forms.

Use of the Hedgehog signaling pathway inhibitor in the treatment of recurrent locally advanced and metastatic basal cell skin cancer

The study objectiveis to provide data on the use of the Hedgehog signaling pathway inhibitor (vismodegib) in the treatment of recurrent locally advanced and metastatic basal cell skin cancer at the N. N. Petrov National Medical Research Center of Oncology.Materials and methods. Clinical data of 10 patients who participated in a multicenter, non-randomized clinical trial of phase II ERIVANCE BBC (ClinicalTrials. gov NCT833417). Patients took the daily studied drug vismodegib orally at a dose of 150 mg daily until disease progression or intolerance due to side effects. Efficiency and safety assessment was carried out once every 4 weeks.Results. Complete regression was achieved in 7 patients, while the average duration of use of the drug was 240 ± 65 days. Stabilization was observed in 2 patients, the minimum duration of the drug was 336 days. One patient showed progression after 728 days of taking the drug. Side effects of the 1 grade according to CTCAE (Common Terminology Criteria for Adverse Events), v. 3.0 were observed in all patients, in 9 they were expressed in muscle cramps, alopecia and changes in taste sensitivity, and in 1 patient isolated in the form of muscle cramps.Conclusion. The results show a good safety profile of vismodegib, which allows it to be used in elderly patients with concomitant pathology. The frequency of response to treatment, including the achievement of complete regression in 70 % of patients, makes vismodegib an acceptable treatment option for metastatic form of basal cell skin cancer and relapse of locally advanced forms.

Comparison of MS inflammatory activity in women using continuous versus cyclic combined oral contraceptives

BackgroundMany women with multiple sclerosis (MS) report fluctuating symptoms across their menstrual cycle. Oral contraceptives (OCs) alter hormonal levels across the menstrual cycle. While cyclic OCs administer hormones for 21 days, followed by a week of placebo, continuous OCs can administer continuous doses of hormones for up to 3 months. Previous studies have suggested that OC use is associated with lower MS-related inflammation. We hypothesized that due to reduced hormonal fluctuations, women with MS might experience less inflammatory activity (clinical relapses+MRI) on continuous OCs than on cyclic OCs. MethodsWe performed a retrospective analysis of prospectively collected data. For women with MS aged 18–50 seen at the UCSF Center for MS and Neuroinflammation, we extracted data on OC use from the Electronic Medical Records (EMR). All variables were confirmed using manual clinical chart review. We identified 19 women with relapsing forms of MS on continuous OCs and matched them (2:1 when possible) to women on cyclic OCs for OC formulation, age, MS duration and DMT type. Inflammatory activity in the two groups was then compared using log-rank tests (time to new relapse, new T2-weighted lesion formation, and gadolinium-enhancing lesion formation) and t-tests (annualized relapse rate). We also performed subgroup analyses in women with at least 1 year (N = 28) and 2 years (N = 21) of clinical observation. A power calculation was performed. ResultsThere was no difference in time to relapse (p = 0.50) between continuous and cycling OC users. However, continuous OC users showed a statistical trend to longer time to T2 lesion formation (p = 0.09) and longer time to contrast-enhancing lesion formation (p = 0.05). In patients with at least 1 year of observation, there was a significant difference in time to T2 lesion formation (p = 0.03) and time to contrast-enhancing lesion formation (p = 0.02). ConclusionIn this exploratory study, women on continuous OCs showed a trend towards less inflammatory activity on MRI relative to women on cyclic OCs. This difference was not reflected in relapse rates. We estimate that 342 patients would be required for an adequately powered cohort study to evaluate such an effect. Our findings provide reassurance that for women using continuous OCs to alleviate menstrual fluctuations in symptoms, there is not an increase in MS-related inflammatory activity.

Effect of Loureirin B on Crohn\u2019s disease rat model induced by TNBS via IL-6/STAT3/NF-\u03baB signaling pathway

BackgroundCrohn’s disease (CD) is a chronic relapsing form of inflammatory bowel disease, seriously threatening human beings health. However, the pathogenesis of CD is still unclear and there is no specific effective drug for treatment of CD. Resina Donis (RD) obtained from Dracaena cochinchinensis (Lour.) S. C. Chen (Liliaceae), has been used for the treatment of CD clinically. Loureirin B (LB) is one of the most important chemical compositions and physiologically active ingredients of resina draconis. It has the molecular structure propan-1-one, 1-(4-hydroxyphenyl)-3-(2,4,6-trimethoxyphenyl)-1-(4-hydroxyphenyl)-3-(2,4,6-trimethoxyphenyl) propan-1-one. The aim of this study was to investigate the effect of LB on CD and explore the underlying mechanisms.Methods and resultsIn this study, the result demonstrated that LB prolonged the survival time of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced rats and alleviated colonic damage in a dose dependent manner. Besides, LB remarkably ameliorated TNBS-induced inflammatory response via regulation of cytokines in the colonic tissues. Moreover, LB could reverse the established fibrosis and impede the accumulation infiltration, and improve the apoptosis induced by TNBS in a dose dependent manner. Further, LB dramatically suppressed TNBS-induced the activation of IL-6/STAT3/NF-κB signaling pathway.ConclusionsThese findings suggested that LB could be beneficial regarding ameliorating TNBS-induced CD, which may represent a novel approach to treat CD and provide an alternative choice for disorders associated with CD.

Investigations of operant ABA renewal during differential reinforcement.

Operant renewal is a form of relapse in which a previously extinguished response recurs due to a change in context. We designed two experiments to examine the impact of differential reinforcement of alternative behavior on ABA renewal in a translational model of relapse with 12 children. We compared levels of renewal in two 3-phase arrangements. In one arrangement, we reinforced target responding in Context A, extinguished responding in Context B, and returned to Context A while continuing to implement extinction. In a second arrangement, an alternative response produced reinforcement in Context B and during the return to Context A. Results across the 2 experiments indicated 3 general findings. First, extinction plus differential reinforcement disrupted target behavior more consistently in Context B relative to extinction alone. Second, renewal tended to be greater and more persistent during extinction alone relative to extinction plus differential reinforcement. Third, the renewal effect appeared to depend on whether the alternative response had a history of extinction in Context A. We discuss methodological implications for the treatment of severe destructive behavior.

Dieulafoy Lesion: Predictive Factors of Early Relapse and Long-Term Follow-Up

Introduction: The Dieulafoy lesion (DL) is a rare cause of gastrointestinal bleeding. Advances in the endoscopy field have allowed an increased rate of detection and therapeutic efficacy. However, doubts remain about the most effective hemostatic approach, the affecting variables of therapeutic failure, and early relapse, as well as in the long-term follow-up. Aims: To assess the efficacy of endoscopic treatment of DL and to identify possible risk factors for early relapse and long-term results. Methods: All patients with DL admitted to a tertiary hospital between 01/01/2007 and 12/31/2018 were evaluated. The form of presentation, associated pathologies, chronic medication, therapeutic approach, and eventual relapse were determined. A telephone interview was conducted for all patients to find out the long-term results. Results: We identified 73 patients with DL, 45 (61.6%) males, with a mean age of 74 ± 15 years. Thirty-nine patients presented the DL in the stomach, 15 in the duodenum, 2 in the small bowel, 3 in the colon, and 11 in the rectum. The median number of endoscopic examinations required for diagnosis was 2. Median Rockall was 4 (range 2–7). After endoscopic treatment, in 95% of the cases, no active bleeding was evident. Only 2 patients required interventional radiology procedures and 1 needed surgery. Fourteen patients (19%) had a rebleeding, 12 during hospitalization and 2 after a median time of 51 months (range 1–117). There was no difference between the groups with and without early relapse in relation to age, gender, hemoglobin values at presentation, presence of shock, associated pathologies, and anticoagulation. Antiplatelet agents intake had a statistically significant relationship with early relapse (p = 0.003). Conclusion: Endoscopic therapy is safe and effective in DL. Patients under antiplatelet therapy are more likely to have an early relapse. The long-term prognosis is excellent, even in patients only treated with endoscopic methods.

Pregnancy Outcomes in Patients Treated with Ocrelizumab

Ocrelizumab (OCR) is a humanised anti‐CD20+ monoclonal antibody approved for the treatment of relapsing and primary progressive forms of multiple sclerosis (MS) and has also been studied in clinical trials for rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). As many patients with MS are women of reproductive age, pregnancy outcomes in OCR‐exposed patients are important. B‐cell levels in neonates exposed to OCR in utero have not been studied in trials, and the effect of OCR on the immune system of the newborn is unknown.

Tacrolimus for Treating Orbital and Cranial Form of Idiopathic Inflammatory Pseudotumors.

Background and PurposeOrbital and cranial form of idiopathic inflammatory pseudotumors (IIPs) are rare disorders with heterogeneous clinical presentations. Corticosteroids have been the first-line treatment for IIPs, but they are not always effective.MethodsWe reviewed the medical records of three patients with orbital or cranial form of IIP who were treated with tacrolimus as an adjuvant treatment.ResultsThe three patients showed favorable outcomes with the addition of tacrolimus, which is a calcineurin inhibitor that inhibits T-cell activation and T-cell-dependent B-cell activation.ConclusionsTacrolimus may be a safe and effective immunosuppressant for refractory or relapsing form of orbital or cranial IIPs.

Teriflunomide preserves peripheral nerve mitochondria from oxidative stress-mediated alterations.

Mitochondrial dysfunction is a common pathological hallmark in various inflammatory and degenerative diseases of the central nervous system, including multiple sclerosis (MS). We previously showed that oxidative stress alters axonal mitochondria, limiting their transport and inducing conformational changes that lead to axonal damage. Teriflunomide (TFN), an oral immunomodulatory drug approved for the treatment of relapsing forms of MS, reversibly inhibits dihydroorotate dehydrogenase (DHODH). DHODH is crucial for de novo pyrimidine biosynthesis and is the only mitochondrial enzyme in this pathway, thus conferring a link between inflammation, mitochondrial activity and axonal integrity.Here, we investigated how DHODH inhibition may affect mitochondrial behavior in the context of oxidative stress. We employed a model of transected murine spinal roots, previously developed in our laboratory. Using confocal live imaging of axonal mitochondria, we showed that in unmanipulated axons, TFN increased significantly the mitochondria length without altering their transport features. In mitochondria challenged with 50 µM hydrogen peroxide (H2O2) to induce oxidative stress, the presence of TFN at 1 µM concentration was able to restore mitochondrial shape, motility, as well as mitochondrial oxidation potential to control levels. No effects were observed at 5 µM TFN, while some shape and motility parameters were restored to control levels at 50 µM TFN.Thus, our data demonstrate an undescribed link between DHODH and mitochondrial dynamics and point to a potential neuroprotective effect of DHODH inhibition in the context of oxidative stress-induced damage of axonal mitochondria.

A case of teriflunomide-induced hepatic injury: assessing causality using available rules

Teriflunomide, a pyrimidine synthesis inhibitor approved for treatment for the relapsing form of multiple sclerosis, has been deemed reasonably safe though hepatic toxicity is a rare serious adverse event. We report an uncommon case of a 48-year-old man who developed severe hepatotoxicity within a short time after initiation of teriflunomide treatment with resolution of signs and symptoms after drug discontinuation and concomitant treatment with cholestyramine. In this case, we provide a general framework regarding the assignment of causation in potential causes of drug-induced liver injury. The patient met the case definition of Hy’s law and his hepatotoxicity was assessed as causally related to teriflunomide using the Roussel Uclaf Causality Assessment Method (RUCAM).

Diroximel fumarate to treat multiple sclerosis.

On October 29, 2019, the Food and Drug Administration (FDA) of the United States approved diroximel fumarate (DRF) as an oral fumarate for the treatment of relapsing forms of multiple sclerosis. Another oral fumarate, dimethyl fumarate (DMF), was approved for the same indication on March 27, 2013. Prior to its approval, DRF did not undergo rigorous testing to determine its efficacy, as its active metabolite, monomethyl fumarate, is the same as that of DMF (bioequivalency). The efficacy, safety and tolerability of DMF have previously been demonstrated in a number of clinical trials and real-world studies. For DRF, one phase III study has been completed, and another is in progress to determine its safety, tolerability and efficacy. In this paper, we review the pharmacology, pharmacokinetics, metabolism, clinical studies and drug safety of DRF.

A review: Multiple Sclerosis Treatment: Current Strategies and Future Hopes

Multiple sclerosis (MS) is a chronic autoimmune disease which influences the neurons of the central nervous system by chronic demyelination. The immune system attacks the myelin sheath and the oligodendrocyte leading to oligodendroglial cells loss, glial scarring and the remyelination stops setting off irreversible damage. The MS is classified into 4 categories: Relapsing–remitting which is considered the most common (about 85% of cases), Secondary progressive, Primary progressive and Progressive-relapsing. The treatment of MS with disease-modifying agents aims to shorten the duration of acute relapses and decreasing relapses frequency. Until now, no curative FDA-approved therapies exist, but there are 8 FDA-approved therapeutic agents able to reduce the disease progression in the relapsing forms of MS. The available therapies are immunosuppressive or immunomodulatory drugs which preclude or delay MS progression. Regenerative medicine via MSCs could play an important role in regeneration a damaged neural tissue as MSCs not only have ability for neurogeneration but also have immunoregulative function which can control and treat MS. Exosomes derived from MSCs offer a good alternative surpassing the possible drawbacks of using MSCs such as tumorigenicity and immune rejection.

Development and Evaluation of Nanoemulsion of Primaquine for Prevention of Relapsing Malaria

Malaria relapsing refers to the reactivation of the infection via Relapse, when symptoms reappear after the parasites have been eliminated from blood but persist as dormant hypnozoites in liver cells. Malaria relapse commonly occurs between 8–24 w and is commonly seen with P. Vivax and P. Ovale infections. Primaquine (PQ) is one of the most widely used antimalarial and is t he only available drug till date to combat relapsing form of malaria especially in case of Plasmodium Vivax and Plasmodium Ovale. Primaquine acts specifically on the pre-erythrocytic schizonts which are concentrated predominantly in the liver and causes relapse after multiplication but one of the major drawback of this drug is that it dissolves in less proportion in systemic circulation to show an active effect. So to reduce these effects, Primaquine incorporated into oral lipid nanoemulsion having particle size in the range of 10–200 nm. The absorbtion capacity of primaquine is significantly increased as nanoemulsion of Primaquine used. The drug is readily absorbed by the liver 45% more than before. So the results declared the successful absorbtion of primaquine by the liver in its nenoemulsion form as it will be used further in the treatment of malaria because it is less toxic.

Protective Effect of Dimethyl Fumarate on Memory Impairment After Cerebral Ischemia-Reperfusion Injury in Rats

BackgroundCerebral ischemia is an important cause of morbidity and mortality worldwide. Dimethyl fumarate (DMF) is indicated for the treatment of patients with relapsing forms of Multiple Sclerosis and psoriasis.ObjectivesIn this study, the effect of DMF on memory and learning impairments and nitrosative stress after cerebral ischemia in rats, was evaluated.MethodsCerebral ischemia was induced via common carotid artery occlusion (CCAO). Rats were randomly divided into three groups (N = 5). Group I included Sham-operated animals who underwent surgery without arterial occlusions, group II (control ischemic) underwent surgery to induce transient global cerebral ischemia for 20 min and received 0.2 - 0.25 mL of distilled water, twice a day by oral gavage, group III included rats which underwent cerebral ischemia and then received DMF (15 mg/kg, twice daily, for 1 week) by oral gavage. Morris water maze test was used to assess spatial memory. Nitric oxide (NO) level in the hippocampus was measured using Griess test.ResultsTreatment of rats with DMF (15 mg/kg, orally, twice daily for 7 days) resulted in a significant decrease in escape latency during training trials. Besides, the time spent in the target quadrant and the number of crossings over the platform area were significantly increased in the DMF-treated rats which were accompanied by a decrease in the proximity to the platform in the probe trial. Furthermore, the results of the Griess assay indicated a significant reduction in the NO levels in the hippocampus of DMF-treated rats.ConclusionsOverall, our findings indicate that DMF improves memory impairment induced by cerebral ischemia/reperfusion injury in rats through the suppression of nitrosative stress in the hippocampus.

Complementary Roles for Ventral Pallidum Cell Types and Their Projections in Relapse.

The ventral pallidum (VP) is a key node in the neural circuits controlling relapse to drug seeking. How this role relates to different VP cell types and their projections is poorly understood. Using male rats, we show how different forms of relapse to alcohol-seeking are assembled from VP cell types and their projections to lateral hypothalamus (LH) and ventral tegmental area (VTA). Using RNAScope in situ hybridization to characterize activity of different VP cell types during relapse to alcohol-seeking provoked by renewal (context-induced reinstatement), we found that VP Gad1 and parvalbumin (PV), but not vGlut2, neurons show relapse-associated changes in c-Fos expression. Next, we used retrograde tracing, chemogenetic, and electrophysiological approaches to study the roles of VPGad1 and VPPV neurons in relapse. We show that VPGad1 neurons contribute to contextual control over relapse (renewal), but not to relapse during reacquisition, via projections to LH, where they converge with ventral striatal inputs onto LHGad1 neurons. This convergence of striatopallidal inputs at the level of individual LHGad1 neurons may be critical to balancing propensity for relapse versus abstinence. In contrast, VPPV neurons contribute to relapse during both renewal and reacquisition via projections to VTA. These findings identify a double dissociation in the roles for different VP cell types and their projections in relapse. VPGad1 neurons control relapse during renewal via projections to LH. VPPV neurons control relapse during both renewal and reacquisition via projections to VTA. Targeting these different pathways may provide tailored interventions for different forms of relapse.SIGNIFICANCE STATEMENT Relapse to drug or reward seeking after a period of extinction or abstinence remains a key impediment to successful treatment. The ventral pallidum, located in the ventral basal ganglia, has long been recognized as an obligatory node in a 'final common pathway' for relapse. Yet how this role relates to the considerable VP cellular and circuit heterogeneity is not well understood. We studied the cellular and circuit architecture for VP in relapse control. We show that different forms of relapse have complementary VP cellular and circuit architectures, raising the possibility that targeting these different neural architectures may provide tailored interventions for different forms of relapse.

Outcomes in a Modern Cohort of Treated Patients with Multiple Sclerosis from Diagnosis Up to 15 Years.

Before disease-modifying therapies (DMTs) were available, the natural history of multiple sclerosis (MS) regarding attainment of accepted disability milestones was reported with fairly wide variance comparing outcomes across studies. The influence of DMTs on these outcomes is unknown. This study aimed to calculate attainment of disability milestones during the first 15 years after onset of DMT-treated relapsing forms of MS (RMS). As a retrospective study, all available disability data (collected routinely) on all newly diagnosed patients with RMS seen and initially diagnosed in a single clinic between 1989 and 2006 were reviewed. Times from first symptoms and diagnosis until first treatment with DMTs were also reviewed. Time-to-event statistics were applied using disability milestones. Mean follow-up of 184 adult patients from symptom onset was 13.7 years. Of patients followed up for 15 years after onset, 16 of 86 (19%) reached an Expanded Disability Status Scale (EDSS) score of 6.0. Estimated median time to reach an EDSS score of 3.0 was 10.7 years and to reach an EDSS score of 4.0 was 18.1 years. There were striking differences between the present results and older data sets and similar results to the few available modern data sets. This analysis of a modern treated RMS cohort provides outcomes data that may be compared favorably with the natural history of RMS.

Dimethyl Fumarate in the Treatment of Relapsing-Remitting Multiple Sclerosis: Patient Reported Outcomes and Perspectives.

Dimethyl fumarate (DMF) is a commonly prescribed oral medication for the treatment of relapsing forms of multiple sclerosis (MS) with a wide range of hypothesized downstream mechanisms of action. Randomized clinical trials have established its clinical efficacy by using standard objective clinical measures. However, MS is a chronic disease that, apart from physical ailments, can affect an individual’s mood, psychosocial status, and quality of life which cannot be captured by using only objective assessment tools. Given the challenge of determining the efficacy of the treatment in a real-world clinical setting, the use of patient-reported outcomes (PROs) may help us to better address these aspects of patient care and establish a more patient-centered approach to MS care. To date, a review of PubMed identified six studies which reported on PROs in patients who are taking DMF. In total, twelve different kinds of PRO measures were utilized and 6359 patients provided at least one form of PRO in these studies. Upon review of these studies, we were able to conclude that people with MS had decreased quality of life compared to the healthy population in the US. MS patients on DMF, however, had better health-related quality of life assessment scores compared to those using a placebo. Previous studies also suggested that DMF decreased work productivity impairment scores after one year of use compared to baseline. DMF was associated with less impairment in fatigue and depression scales along with improved treatment quality assessment and adherence scores. This review will present a brief synopsis of the published literature and will provide indications for future directions with respect to PROs and DMF in people with MS.

Dimethyl Fumarate: A Review in Relapsing-Remitting MS.

Dimethyl fumarate (Tecfidera®) is approved for the treatment of relapsing forms of multiple sclerosis (MS). Based on evidence from the clinical trial and real-world settings, dimethyl fumarate is an effective treatment in this patient population, with benefits maintained over the longer term. In the pivotal, placebo-controlled phaseIII DEFINE and CONFIRM trials in adults with relapsing-remitting multiple sclerosis (RRMS), twice-daily dimethyl fumarate reduced clinical relapse and MRI measures of disease activity and improved some aspects of health-related quality of life (HR-QoL). Reduced disability progression was also observed with dimethyl fumarate in DEFINE. Results in predominantly East Asian patients (APEX trial) were reflective of those seen in DEFINE and CONFIRM. Dimethyl fumarate had an acceptable tolerability profile. The most common adverse events were flushing and gastrointestinal events, which were of mild or moderate severity and appear to be largely manageable. Thus twice-daily dimethyl fumarate remains an effective treatment option for use in patients with RRMS, with the convenience of oral administration.

Analysis of cardiac monitoring and safety data in patients initiating fingolimod treatment in the home or in clinic

BackgroundFingolimod (Gilenya®) is approved for relapsing forms of multiple sclerosis in the USA. Owing to transient heart-rate effects when initiating fingolimod, eligible patients undergo precautionary baseline assessment and first-dose observation (FDO) for ≥6 h. Prior to 2014, FDO was undertaken only in clinics. As the FDO period is short, and fingolimod has accumulated evidence of a positive benefit:risk ratio, an in-home treatment-initiation program, Gilenya@Home, was developed to offer a convenient alternative.MethodsCardiac parameters and adverse events (AEs) were recorded by healthcare professionals performing fingolimod FDOs in the US Gilenya@Home program or in US Gilenya Assessment Network clinics. Anonymized data were collated retrospectively from the first 34 months in the home setting and from 78 months in clinics; data are reported descriptively. Satisfaction with Gilenya@Home was rated by patients using a 7-item questionnaire that considered aspects such as ease of scheduling, courtesy, and competency.ResultsData were captured as part of standard care from 5573 patients initiating fingolimod in-home (October 2014 to July 2017) and from 15,025 patients initiating in-clinic (July 2010 to December 2016). In the Gilenya@Home questionnaire, 91.7% of 1848 respondents rated their overall satisfaction as “very good,” and 7.6% rated their satisfaction as “good.” AEs were reported for 30.7 and 32.6% of in-home and in-clinic patients, respectively. In total, 557 in-home (10.0%) and 398 in-clinic (2.6%) patients were monitored for > 6 h; 15 (0.3%) in-home and 129 (0.9%) in-clinic patients were transferred to an emergency room for overnight monitoring. The mean (standard deviation) heart rate (HR; bpm) pre-FDO was 74.8 (12.2) in-home and 74.2 (11.3) in-clinic; reduction in HR at 6 h postdose was 10.6 (12.0) and 6.3 (9.6), respectively. New-onset first-degree atrioventricular block was experienced by 132 (2.4%) in-home and 74 (0.5%) in-clinic patients, and Wenckebach (Mobitz type I) second-degree atrioventricular block by four (0.07%) and nine (0.1%) patients, with no cases of third-degree atrioventricular block.ConclusionsA substantial number of patients have initiated fingolimod at home, reporting very high levels of satisfaction. Gilenya@Home was as rigorous as the clinic setting in detecting cardiovascular events. Overall, FDO safety outcomes were similar with Gilenya@Home and in-clinic.