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Verbout NG, Su W, Pham P, Jordan K, Kohs TC, Tucker EI, McCarty OJ, Sherman LS. E-WE thrombin, a protein C activator, reduces disease severity and spinal cord inflammation in relapsing-remitting murine experimental autoimmune encephalomyelitis. RESEARCH SQUARE 2023:rs.3.rs-2802415. [PMID: 37131631 PMCID: PMC10153372 DOI: 10.21203/rs.3.rs-2802415/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
Objective Relapses in patients with relapsing-remitting multiple sclerosis (RRMS) are typically treated with high-dose corticosteroids including methylprednisolone. However, high-dose corticosteroids are associated with significant adverse effects, can increase the risk for other morbidities, and often do not impact disease course. Multiple mechanisms are proposed to contribute to acute relapses in RRMS patients, including neuroinflammation, fibrin formation and compromised blood vessel barrier function. The protein C activator, E-WE thrombin is a recombinant therapeutic in clinical development for its antithrombotic and cytoprotective properties, including protection of endothelial cell barrier function. In mice, treatment with E-WE thrombin reduced neuroinflammation and extracellular fibrin formation in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). We therefore tested the hypothesis that E-WE thrombin could reduce disease severity in a relapsing-remitting model of EAE. Methods Female SJL mice were inoculated with proteolipid protein (PLP) peptide and treated with E-WE thrombin (25 μg/kg; iv) or vehicle at onset of detectable disease. In other experiments, E-WE thrombin was compared to methylprednisolone (100 mg/kg; iv) or the combination of both. Results Compared to vehicle, administration of E-WE thrombin significantly improved disease severity of the initial attack and relapse and delayed onset of relapse as effectively as methylprednisolone. Both methylprednisolone and E-WE thrombin reduced demyelination and immune cell recruitment, and the combination of both treatments had an additive effect. Conclusion The data presented herein demonstrate that E-WE thrombin is protective in mice with relapsing-remitting EAE, a widely used model of MS. Our data indicate that E-WE thrombin is as effective as high-dose methylprednisolone in improving disease score and may exert additional benefit when administered in combination. Taken together, these data suggest that E-WE thrombin may be an effective alternative to high-dose methylprednisolone for managing acute MS attacks.
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Affiliation(s)
| | - Weiping Su
- Oregon National Primate Research Center, Oregon Health & Science University
| | - Peter Pham
- Oregon National Primate Research Center, Oregon Health & Science University
| | | | | | | | | | - Larry S Sherman
- Oregon National Primate Research Center, Oregon Health & Science University
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Patti F, Chisari CG, Toscano S, Annovazzi P, Banfi P, Bergamaschi R, Clerici R, Conti MZ, Cortese A, Fantozzi R, Ferraro D, Fischetti M, Frigo M, Gatto M, Immovilli P, Leoni S, Malucchi S, Maniscalco G, Marfia GA, Paolicelli D, Perini P, Serrati C, Totaro R, Turano G, Valentino P, Zaffaroni M, Zuliani C, Centonze D. Patients with multiple sclerosis choose a collaborative role in making treatment decision: results from the Italian multicenter SWITCH study. Mult Scler Relat Disord 2023; 70:104474. [PMID: 36584654 DOI: 10.1016/j.msard.2022.104474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 12/14/2022] [Accepted: 12/18/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Clinicians are increasingly recognizing the importance of shared decision-making in complex treatment choices, highlighting the importance of the patient's rationale and motivation for switching therapies. This study aimed to evaluate the association between different modalities of changing multiple sclerosis (MS) treatments, cognitive profile and attitude and preferences of patients concerning treatment choice. METHODS This multicenter cross-sectional study was conducted at 28 Italian MS centers in the period between June 2016 and June 2017. We screened all MS patients treated with any DMT, with a treatment compliance of at least 80% of therapy administered during the 3 last months who needed to modify MS therapy because of efficacy, safety or other reasons during a follow-up visit. At the time of switching the symbol digit modalities test (SDMT) and the Control Preference Scale (CPS) were evaluated. According to the CPS, patients were classified as "active" (i.e. who prefer making the medical decision themselves), "collaborative" (i.e. who prefer decisions be made jointly with the physician), or "passive" (i.e. who prefer the physician make the decision). RESULTS Out of 13,657 patients recorded in the log, 409 (3%) changed therapy. Of these, 336 (2.5%) patients, 69.6% were female and with mean age 40.6 ± 10.5 years, were enrolled. According to the CPS score evaluation, a significant high percentage of patients (51.1%) were considered collaborative, 74 patients (22.5%) were passive, and 60 (18.2%) patients were active. Stratifying according to CPS results, we found a higher SDMT score among collaborative patients compared to active and passive ones (45.8 ± 12.3 versus 41.0 ± 13.2 versus 41.7 ± 12.8, p < 0.05). CONCLUSION In this study, the CPS evaluation showed that more than 50% of patients who needed to change therapy chose a "collaborative" role in making treatment decision. Cognitive profile with SDMT seems to correlate with patients' preference on treatment decision, showing better scores in collaborative patients.
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Affiliation(s)
- Francesco Patti
- Department "GF Ingrassia" Section of Neurosciences, University of Catania, via S. Sofia 78, Catania 95129, Italy.
| | - Clara Grazia Chisari
- Department "GF Ingrassia" Section of Neurosciences, University of Catania, Catania, Italy
| | - Simona Toscano
- Department "GF Ingrassia" Section of Neurosciences, University of Catania, via S. Sofia 78, Catania 95129, Italy
| | - Pietro Annovazzi
- Multiple Sclerosis Center, Hospital of Gallarate - ASST della Valle Olona, Gallarate, Italy
| | - Paola Banfi
- Operative Unit of Neurology and Stroke Unit, Varese, Italy
| | | | | | | | - Antonio Cortese
- Department of Human Neurosciences, Sapienza, University of Rome, Italy
| | | | - Diana Ferraro
- Department of Neuroscience, UO of Neurology, AOU Policlinico OB, Modena, Italy
| | | | - Maura Frigo
- Neurology Department, San Gerardo Hospital, Monza, Italy
| | - Maurizia Gatto
- Department of Neurology, General Regional Hospital "Miulli", Acquaviva delle Fonti, Bari, Italy
| | - Paolo Immovilli
- Emergency Department, Neurology Unit, G. da Saliceto Hospital, Piacenza, Italy
| | | | - Simona Malucchi
- SCDO Neurologia-CRESM, University Hospital San Luigi Gonzaga, Orbassano, Turin, Italy
| | | | - Girolama Alessandra Marfia
- Department of Systems Medicine, Multiple Sclerosis Clinical & Research Center, "Tor Vergata" University, Rome, Italy
| | - Damiano Paolicelli
- Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari "Aldo Moro", Bari, Italy
| | - Paola Perini
- Multiple Sclerosis Center, Neurological Clinic, University Hospital of Padua, Italy
| | - Carlo Serrati
- Operative Unit of Neurology and Stroke Unit, IRCCS Hospital San Martino, Genoa, Italy
| | - Rocco Totaro
- Department of Neurology, Demyelinating Disease Center, San Salvatore Hospital, L'Aquila, Italy
| | - Gabriella Turano
- Department of Neurology, Mondovì General Hospital, Local Health Authority CN1, Mondovì, Cuneo, Italy
| | | | - Mauro Zaffaroni
- Multiple Sclerosis Center, Hospital of Gallarate - ASST della Valle Olona, Gallarate, Italy
| | | | - Diego Centonze
- Department "GF Ingrassia" Section of Neurosciences, University of Catania, Catania, Italy; Unit of Neurology - IRCCS Neuromed, Pozzilli, Isernia, Italy.
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Casanova B, Quintanilla-Bordás C, Gascón F. Escalation vs. Early Intense Therapy in Multiple Sclerosis. J Pers Med 2022; 12:119. [PMID: 35055434 PMCID: PMC8778390 DOI: 10.3390/jpm12010119] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/28/2021] [Accepted: 01/01/2022] [Indexed: 02/01/2023] Open
Abstract
The treatment strategy of multiple sclerosis (MS) is a highly controversial debate. Currently, there are up to 19 drugs approved. However, there is no clear evidence to guide fundamental decisions such as what treatment should be chosen in first place, when treatment failure or suboptimal response should be considered, or what treatment should be considered in these cases. The "escalation strategy" consists of starting treatment with drugs of low side-effect profile and low efficacy, and "escalating" to drugs of higher efficacy-with more potential side-effects-if necessary. This strategy has prevailed over the years. However, the evidence supporting this strategy is based on short-term studies, in hope that the benefits will stand in the long term. These studies usually do not consider the heterogeneity of the disease and the limited effect that relapses have on the long-term. On the other hand, "early intense therapy" strategy refers to starting treatment with drugs of higher efficacy from the beginning, despite having a less favorable side-effect profile. This approach takes advantage of the so-called "window of opportunity" in hope to maximize the clinical benefits in the long-term. At present, the debate remains open. In this review, we will critically review both strategies. We provide a summary of the current evidence for each strategy without aiming to reach a definite conclusion.
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Affiliation(s)
- Bonaventura Casanova
- Unitat de Neuroimmunologia, Hospital Universitari i Politècnic La Fe. València, la Universitat de València, 46026 Valencia, Spain;
| | - Carlos Quintanilla-Bordás
- Unitat de Neuroimmunologia, Hospital Universitari i Politècnic La Fe. València, la Universitat de València, 46026 Valencia, Spain;
| | - Francisco Gascón
- Unitat de Neuroimmunologia, Hospital Clínic Universitari de València, 46010 Valencia, Spain;
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Lees S, Dicker M, Ku JE, Chaganti V, Mew-Sum M, Wang N, Smith A, Oldmeadow C, Goon WL, Bevan M, Lang D, Hinwood M. Impact of disease-modifying therapies on MRI and neurocognitive outcomes in relapsing-remitting multiple sclerosis: a protocol for a systematic review and network meta-analysis. BMJ Open 2021; 11:e051509. [PMID: 34728450 PMCID: PMC8565566 DOI: 10.1136/bmjopen-2021-051509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
INTRODUCTION Disease-modifying therapies (DMTs) are the mainstay of treatment for relapsing-remitting multiple sclerosis (RRMS). There is established evidence that DMTs are effective at reducing relapse rate and disease progression in RRMS, but there has been less consideration to the synthesis of MRI and neurocognitive outcomes, which play an increasingly important role in treatment decisions. The aim of this systematic review and network meta-analysis is to examine the relative efficacy, acceptability and tolerability of DMTs for RRMS, using MRI and neurocognitive outcomes. METHODS AND ANALYSIS We will search electronic databases, including MEDLINE, Embase and the Cochrane Central Register of Controlled Trials, with no date restrictions. We will also search the websites of international regulatory bodies for pharmaceuticals and international trial registries. We will include parallel group randomised controlled trials of DMTs including interferon beta-1a intramuscular, interferon beta-1a subcutaneous, interferon beta-1b, peginterferon beta-1a, glatiramer acetate, natalizumab, ocrelizumab, alemtuzumab, dimethyl fumarate, teriflunomide, fingolimod, cladribine, ozanimod, mitoxantrone and rituximab, either head-to-head or against placebo in adults with RRMS. Primary outcomes include efficacy (MRI outcomes including new T1/hypointense lesions and T2/hyperintense lesions) and acceptability (all-cause dropouts). Secondary outcomes include gadolinium-enhancing lesions, cerebral atrophy and tolerability (dropouts due to adverse events). Neurocognitive measures across three domains including processing speed, working memory and verbal learning will be included as exploratory outcomes. Data will be analysed using a random-effects pairwise meta-analysis and a Bayesian hierarchical random effects network meta-analysis to evaluate the efficacy, acceptability and tolerability of the included DMTs. Subgroup and sensitivity analyses will be conducted to assess the robustness of the findings. The review will be reported using the Preferred Reporting Items for Systematic Reviews incorporating Network Meta-Analyses statement. ETHICS AND DISSEMINATION This protocol does not require ethics approval. Results will be disseminated in a peer-reviewed academic journal. PROSPERO REGISTRATION NUMBER CRD42021239630.
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Affiliation(s)
- Samuel Lees
- School of Medicine and Public Health, The University of Newcastle, Callaghan, New South Wales, Australia
| | - Mathew Dicker
- School of Medicine and Public Health, The University of Newcastle, Callaghan, New South Wales, Australia
| | - Jie En Ku
- School of Medicine and Public Health, The University of Newcastle, Callaghan, New South Wales, Australia
| | - Varun Chaganti
- School of Medicine and Public Health, The University of Newcastle, Callaghan, New South Wales, Australia
| | - Matthew Mew-Sum
- School of Medicine and Public Health, The University of Newcastle, Callaghan, New South Wales, Australia
| | - Nick Wang
- School of Medicine and Public Health, The University of Newcastle, Callaghan, New South Wales, Australia
| | - Angela Smith
- HNEHealth Libraries, Hunter New England Local Health District, New Lambton, New South Wales, Australia
| | | | - Wooi Lynn Goon
- School of Medicine and Public Health, The University of Newcastle, Callaghan, New South Wales, Australia
| | - Marc Bevan
- School of Medicine and Public Health, The University of Newcastle, Callaghan, New South Wales, Australia
| | - Danielle Lang
- School of Medicine and Public Health, The University of Newcastle, Callaghan, New South Wales, Australia
- Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia
| | - Madeleine Hinwood
- School of Medicine and Public Health, The University of Newcastle, Callaghan, New South Wales, Australia
- Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia
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Callegari I, Derfuss T, Galli E. Update on treatment in multiple sclerosis. Presse Med 2021; 50:104068. [PMID: 34033862 DOI: 10.1016/j.lpm.2021.104068] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 03/29/2021] [Accepted: 05/06/2021] [Indexed: 11/17/2022] Open
Abstract
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. In recent years, many disease-modifying therapies (DMT) have been approved for MS treatment. For this reason, a profound knowledge of the characteristics and indications of the available compounds is required to tailor the therapeutic strategy to the individual patient characteristics. This should include the mechanism of action and pharmacokinetic of the drug, the safety and efficacy profile provided by clinical trials, as well as the understanding of possible side effects. Moreover, the evolving knowledge of the disease is paving the way to new and innovative therapeutic approaches, as well as the development of new biomarkers to monitor the therapeutic response and to guide the clinician's therapeutic choices. In this review we provide a comprehensive overview on currently approved therapies in MS and the emerging evidence-based strategies to adopt for initiating, monitoring, and eventually adapting a therapeutic regimen with DMT.
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Affiliation(s)
- Ilaria Callegari
- Department of Biomedicine, University Hospital Basel, University of Basel, Hebelstrasse 20, 4031 Basel, Switzerland
| | - Tobias Derfuss
- Department of Biomedicine, University Hospital Basel, University of Basel, Hebelstrasse 20, 4031 Basel, Switzerland; Department of Neurology, University Hospital Basel, University of Basel, Petersgraben 4, 4031 Basel, Switzerland.
| | - Edoardo Galli
- Department of Biomedicine, University Hospital Basel, University of Basel, Hebelstrasse 20, 4031 Basel, Switzerland; Department of Neurology, University Hospital Basel, University of Basel, Petersgraben 4, 4031 Basel, Switzerland
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Cohan SL, Hendin BA, Reder AT, Smoot K, Avila R, Mendoza JP, Weinstock-Guttman B. Interferons and Multiple Sclerosis: Lessons from 25 Years of Clinical and Real-World Experience with Intramuscular Interferon Beta-1a (Avonex). CNS Drugs 2021; 35:743-767. [PMID: 34228301 PMCID: PMC8258741 DOI: 10.1007/s40263-021-00822-z] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/28/2021] [Indexed: 12/15/2022]
Abstract
Recombinant interferon (IFN) β-1b was approved by the US Food and Drug Administration as the first disease-modifying therapy (DMT) for multiple sclerosis (MS) in 1993. Since that time, clinical trials and real-world observational studies have demonstrated the effectiveness of IFN therapies. The pivotal intramuscular IFN β-1a phase III trial published in 1996 was the first to demonstrate that a DMT could reduce accumulation of sustained disability in MS. Patient adherence to treatment is higher with intramuscular IFN β-1a, given once weekly, than with subcutaneous formulations requiring multiple injections per week. Moreover, subcutaneous IFN β-1a is associated with an increased incidence of injection-site reactions and neutralizing antibodies compared with intramuscular administration. In recent years, revisions to MS diagnostic criteria have improved clinicians' ability to identify patients with MS and have promoted the use of magnetic resonance imaging (MRI) for diagnosis and disease monitoring. MRI studies show that treatment with IFN β-1a, relative to placebo, reduces T2 and gadolinium-enhancing lesions and gray matter atrophy. Since the approval of intramuscular IFN β-1a, a number of high-efficacy therapies have been approved for MS, though the benefit of these high-efficacy therapies should be balanced against the increased risk of serious adverse events associated with their long-term use. For some subpopulations of patients, including pregnant women, the safety profile of IFN β formulations may provide a particular benefit. In addition, the antiviral properties of IFNs may indicate potential therapeutic opportunities for IFN β in reducing the risk of viral infections such as COVID-19.
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Affiliation(s)
- Stanley L. Cohan
- Providence Multiple Sclerosis Center, Providence Brain and Spine Institute, Portland, OR USA
| | | | | | - Kyle Smoot
- Providence Multiple Sclerosis Center, Providence Brain and Spine Institute, Portland, OR USA
| | | | | | - Bianca Weinstock-Guttman
- Department of Neurology, Jacobs Comprehensive MS Treatment and Research Center, Jacobs School of Medicine and Biomedical Sciences, State University of New York, 1010 Main St., 2nd floor, Buffalo, NY, 14202, USA.
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7
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Blais LL, Montgomery TL, Amiel E, Deming PB, Krementsov DN. Probiotic and commensal gut microbial therapies in multiple sclerosis and its animal models: a comprehensive review. Gut Microbes 2021; 13:1943289. [PMID: 34264791 PMCID: PMC8284149 DOI: 10.1080/19490976.2021.1943289] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 05/18/2021] [Accepted: 06/07/2021] [Indexed: 02/04/2023] Open
Abstract
The need for alternative treatments for multiple sclerosis (MS) has triggered copious amounts of research into microbial therapies focused on manipulating the microbiota-gut-brain axis. This comprehensive review was intended to present and systematically evaluate the current clinical and preclinical evidence for various probiotic and commensal gut microbial therapies as treatments for MS, using the Bradford Hill criteria (BHC) as a multi-parameter assessment rubric. Literature searches were performed to identify a total of 37 relevant studies (6 human, 31 animal), including 28 probiotic therapy and 9 commensal therapy studies. In addition to presenting qualitative summaries of these findings, therapeutic evidence for each bacterial formulation was assessed using the BHC to generate summative scores. These scores, which encompassed study quality, replication, and other considerations, were used to rank the most promising therapies and highlight deficiencies. Several therapeutic formulations, including VSL#3, Lactobacillus paracasei, Bifidobacterium animalis, E. coli Nissle 1917, and Prevotella histicola, emerged as the most promising. In contrast, a number of other therapies were hindered by limited evidence of replicable findings and other criteria, which need to be addressed by future studies in order to harness gut microbial therapies to ultimately provide cheaper, safer, and more durable treatments for MS.
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Affiliation(s)
- Lorrie L. Blais
- Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT, USA
| | - Theresa L. Montgomery
- Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT, USA
| | - Eyal Amiel
- Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT, USA
| | - Paula B. Deming
- Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT, USA
| | - Dimitry N. Krementsov
- Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT, USA
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8
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Patti F, Chisari CG, D'Amico E, Annovazzi P, Banfi P, Bergamaschi R, Clerici R, Conti MZ, Cortese A, Fantozzi R, Fischetti M, Frigo M, Gatto M, Immovilli P, Leoni S, Malucchi S, Maniscalco G, Marfia GA, Paolicelli D, Perini P, Serrati C, Sola P, Totaro R, Turano G, Valentino P, Zaffaroni M, Zuliani C, Centonze D. Clinical and patient determinants of changing therapy in relapsing-remitting multiple sclerosis (SWITCH study). Mult Scler Relat Disord 2020; 42:102124. [DOI: 10.1016/j.msard.2020.102124] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 03/14/2020] [Accepted: 03/29/2020] [Indexed: 10/24/2022]
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Filipi M, Jack S. Interferons in the Treatment of Multiple Sclerosis: A Clinical Efficacy, Safety, and Tolerability Update. Int J MS Care 2019; 22:165-172. [PMID: 32863784 DOI: 10.7224/1537-2073.2018-063] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Interferon beta (IFNβ) was the first disease-modifying therapy available to treat multiple sclerosis (MS), providing patients with a treatment that resulted in reduced relapse rates and delays in the onset of disability. Four IFNβ drugs are currently approved to treat relapsing forms of MS: subcutaneous (SC) IFNβ-1b, SC IFNβ-1a, intramuscular IFNβ-1a, and, most recently, SC peginterferon beta-1a. Peginterferon beta-1a has an extended half-life and requires less frequent administration than other available treatments (once every 2 weeks vs every other day, 3 times per week, or weekly). Large randomized controlled clinical trials have confirmed the efficacy of interferons for the treatment of relapsing MS. The most frequent adverse events in patients receiving IFNs include injection site reactions and flu-like symptoms. Patient education and mitigation strategies are key to managing these adverse events and supporting therapy adherence. With fewer injections needed, peginterferon beta-1a is associated with less frequent discomfort, which may translate to improved adherence, a major factor in treatment efficacy. Because the available interferon therapies differ in administration route and frequency of injection, switching among these therapies may be a viable option for patients who experience issues with tolerability. Although a variety of disease-modifying therapies are now available to treat relapsing MS, the efficacy and long-term safety profile of interferons make them an important first-line option for treatment.
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Freedman MS, Duquette P, Grand'Maison F, Lee L, Vorobeychik G, Lara N, Khurana V, Nakhaipour HR, Schecter R, Haddad P. The clinical and cost impact of switching to fingolimod versus other first line injectable disease-modifying therapies in patients with relapsing multiple sclerosis. Curr Med Res Opin 2019; 35:767-776. [PMID: 30614288 DOI: 10.1080/03007995.2019.1565818] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
BACKGROUND There is limited evidence on the effectiveness and healthcare costs of switching to fingolimod versus another first line injectable therapy (FLIT) in patients with relapsing multiple sclerosis (RMS) who have already been treated with FLIT. OBJECTIVE The objectives of the study were to assess the annualized relapse rate (ARR), socio-demographic and clinical characteristics, persistence and adherence rates, healthcare resource utilization and cost among patients with RMS who either switch to fingolimod or another FLIT in routine clinical practice. METHODS A multicenter, observational, retrospective chart review was conducted across eight clinics in Canada between 1 May 2011 and 30 June 2013. The data was collected from two cohorts: patients who switched to fingolimod and patients who switched to FLIT from a previous FLIT. RESULTS AND CONCLUSIONS A total of 124 patients were included in the study: 82 and 42 switched to fingolimod and FLIT, respectively. There were no significant differences in the patient characteristics at the date of switch except for number of previous disease-modifying therapies (DMTs) which was higher in the fingolimod cohort (fingolimod: 1.52; FLIT: 1.10, p < .001). The ARR during the first year of switching was numerically higher in the FLIT cohort compared to the fingolimod cohort (FLIT: 0.9 [95% CI 0.3-1.6]; fingolimod: 0.3 [95% CI 0.1-0.5]). The negative binomial model adjusted for the number of previous DMTs confirmed a statistically significant difference in ARR between the fingolimod and FLIT cohorts at 12 months of follow-up (p = .012). In the fingolimod cohort, 20.7% of patients experienced at least one relapse compared to 38.1% in the FLIT cohort. In both groups, a high proportion of patients (>90%) showed good treatment adherence (≥80% of prescribed doses).
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Affiliation(s)
- M S Freedman
- a University of Ottawa and The Ottawa Hospital Research Institute , Ottawa , Ontario , Canada
| | - P Duquette
- b Notre Dame Hospital , Université de Montréal , Montreal , Quebec , Canada
| | - F Grand'Maison
- c Neuro-Rive Sud Clinic , Greenfield Park , Quebec , Canada
| | - L Lee
- d Sunnybrook Health Sciences Centre , University of Toronto , Toronto , Ontario , Canada
| | - G Vorobeychik
- e Fraser Health Multiple Sclerosis Clinic Burnaby Hospital , Burnaby , British Columbia , Canada
| | - N Lara
- f IQVIA , Barcelona , Spain
| | - V Khurana
- g Novartis Healthcare Private Limited , Hyderabad , India
| | - H R Nakhaipour
- h Novartis Pharmaceuticals Canada Inc ., Dorval , Quebec , Canada
| | - R Schecter
- h Novartis Pharmaceuticals Canada Inc ., Dorval , Quebec , Canada
| | - P Haddad
- h Novartis Pharmaceuticals Canada Inc ., Dorval , Quebec , Canada
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11
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Deleu D, Mesraoua B, Canibaño B, Melikyan G, Al Hail H, El-Sheikh L, Ali M, Al Hussein H, Ibrahim F, Hanssens Y. Oral disease-modifying therapies for multiple sclerosis in the Middle Eastern and North African (MENA) region: an overview. Curr Med Res Opin 2019; 35:249-260. [PMID: 29764226 DOI: 10.1080/03007995.2018.1476334] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
Abstract
BACKGROUND The introduction of new disease-modifying therapies (DMTs) for remitting-relapsing multiple sclerosis (RRMS) has considerably transformed the landscape of therapeutic opportunities for this chronic disabling disease. Unlike injectable drugs, oral DMTs promote patient satisfaction and increase therapeutic adherence. REVIEW This article reviews the salient features about the mode of action, efficacy, safety, and tolerability profile of approved oral DMTs in RRMS, and reviews their place in clinical algorithms in the Middle East and North Africa (MENA) region. A systematic review was conducted using a comprehensive search of MEDLINE, PubMed, Cochrane Database of Systematic Reviews (period January 1, 1995-January 31, 2018). Additional searches of the American Academy of Neurology and European Committee for Treatment and Research in Multiple Sclerosis abstracts from 2012-2017 were performed, in addition to searches of the Food and Drug Administration and European Medicines Agency websites, to obtain relevant safety information on these DMTs. CONCLUSIONS Four oral DMTs: fingolimod, teriflunomide, dimethyl fumarate, and cladribine have been approved by the regulatory agencies. Based on the number needed to treat (NNT), the potential role of these DMTs in the management of active and highly active or rapidly evolving RRMS is assessed. Finally, the place of the oral DMTs in clinical algorithms in the MENA region is reviewed.
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Affiliation(s)
- Dirk Deleu
- a Department of Neurology , Neuroscience Institute, Hamad Medical Corporation , Doha , State of Qatar
| | - Boulenouar Mesraoua
- a Department of Neurology , Neuroscience Institute, Hamad Medical Corporation , Doha , State of Qatar
| | - Beatriz Canibaño
- a Department of Neurology , Neuroscience Institute, Hamad Medical Corporation , Doha , State of Qatar
| | - Gayane Melikyan
- a Department of Neurology , Neuroscience Institute, Hamad Medical Corporation , Doha , State of Qatar
| | - Hassan Al Hail
- a Department of Neurology , Neuroscience Institute, Hamad Medical Corporation , Doha , State of Qatar
| | - Lubna El-Sheikh
- a Department of Neurology , Neuroscience Institute, Hamad Medical Corporation , Doha , State of Qatar
| | - Musab Ali
- a Department of Neurology , Neuroscience Institute, Hamad Medical Corporation , Doha , State of Qatar
| | - Hassan Al Hussein
- a Department of Neurology , Neuroscience Institute, Hamad Medical Corporation , Doha , State of Qatar
| | - Faiza Ibrahim
- a Department of Neurology , Neuroscience Institute, Hamad Medical Corporation , Doha , State of Qatar
| | - Yolande Hanssens
- b Department of Clinical Services Unit , Corporate Pharmacy, Hamad Medical Corporation , Doha , State of Qatar
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Chalmer TA, Kalincik T, Laursen B, Sorensen PS, Magyari M. Treatment escalation leads to fewer relapses compared with switching to another moderately effective therapy. J Neurol 2018; 266:306-315. [DOI: 10.1007/s00415-018-9126-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 11/08/2018] [Accepted: 11/13/2018] [Indexed: 10/27/2022]
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Chen C, Wu N, Watson C. Multiple sclerosis patients who are stable on interferon therapy show better outcomes when staying on same therapy than patients who switch to another interferon. CLINICOECONOMICS AND OUTCOMES RESEARCH 2018; 10:723-730. [PMID: 30464565 PMCID: PMC6219109 DOI: 10.2147/ceor.s163907] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Background Real-world outcomes from staying on an interferon beta (IFNβ) vs switching to another IFNβ could help guide treatment decisions. This study's objective was to compare outcomes of stable multiple sclerosis (MS) patients on an IFNβ who stayed on therapy vs those who switched to another IFNβ. Methods MS patients were identified from the Optum Insights Clinformatics Data Mart Multi-Plan who were 18-64 years old and relapse-free (stable) over 1 year while continuously being treated with an IFNβ. Patients were propensity score matched 3:1 using age, gender, initial IFNβ, adherence, and month and year for patients who stayed on the initial IFNβ (No Switch) to patients who switched to another IFNβ (Switch). Patients had to be continuously enrolled for 1 year prior to and 1 year after the index date (date of the first claim of the switched-to IFNβ or the match date when continuing on initial IFNβ treatment). Patients were enrolled with index dates between January 1, 2005 and September 30, 2014. Relapses were recorded during the 1-year follow-up period after index date. Results After matching, there were 381 patients in the Switch group and 1,143 in the No Switch group. Baseline characteristics were well matched between groups (average age 46 years, 72% female). The percentage of patients experiencing a relapse during the follow-up was significantly higher in the Switch group than in the No Switch group (21% vs 12%, P<0.0001). Annual relapse rate during the follow-up was significantly higher in the Switch group than in the No Switch group (0.35 vs 0.20, P<0.0001). Conclusion MS patients stable on IFNβ therapy who remain on initial therapy had significantly better outcomes (lower annual relapse rate and percentage of patients with relapses) than patients who switched to another IFNβ. This supports the benefits of allowing patients to remain on current IFNβ therapy when stable.
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Affiliation(s)
- Chao Chen
- Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Ning Wu
- Value and Access, Biogen, Cambridge, MA, USA,
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Comparative effectiveness of dimethyl fumarate versus fingolimod and teriflunomide among MS patients switching from first-generation platform therapies in the US. Mult Scler Relat Disord 2018; 27:101-111. [PMID: 30368221 DOI: 10.1016/j.msard.2018.09.038] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 09/28/2018] [Accepted: 09/29/2018] [Indexed: 01/04/2023]
Abstract
BACKGROUND Previous real-world comparative research of MS disease modifying therapies (DMTs) in the overall population has suggested dimethyl fumarate (DMF) to be comparable to fingolimod (FTY) and more efficacious than teriflunomide (TERI) in reducing relapses. However, there is limited comparative evidence in patients switching from platform DMTs in the US. The objective of the study was to compare the annualized relapse rate (ARR) and risk of relapse in MS patients who have switched from a platform therapy to DMF, FTY, or TERI. METHODS MS patients (18-65 years old) initiating an oral DMT from June 2013 to March 2015 were identified from the Truven MarketScan® Commercial Claims Database. The index date was the date of first oral DMT fill. Patients were required to have: continuous enrollment in the database for 12 months pre-index date and ≥3 months post-index date; ≥1 MS diagnosis over the pre-index period; discontinuation of a platform DMT with no evidence of oral or infusion DMTs over the pre-index period; and adherence to the index drug for ≥90 days. DMF patients were propensity-score matched (PSM) 3:1 to FTY and to TERI based on age, gender, region, a claims-based MS severity measure, ARR, and number of hospitalizations over the pre-index period. Patients were censored when they dropped out of the database or at the end of the study period (March 31, 2016). Post-index relapses were annualized. RESULTS The database included 20,311 oral DMT users. After applying the study criteria, the PSM yielded 1602:534 switch patients for the DMF-FTY matched cohort. DMF-FTY patients were well-matched on all covariates: age (mean = 44 for both), gender (28% vs. 26% male, respectively), MS severity measure (0.99 vs. 1.08), and baseline ARR (0.40 vs. 0.44). PSM yielded 833:279 switch patients for the DMF-TERI match. DMF-TERI patients were well-matched on all covariates: age (mean = 50), gender (24% vs. 25% male), MS severity measure (0.86 vs. 0.99), and baseline ARR (0.23 vs. 0.30). The standardized differences confirmed balance across all covariates for matched cohorts. The matched DMF-FTY cohorts had comparable post-index ARR (Rate Ratio [RR] = 1.07 [95% Cl: 0.861, 1.328]) and risk of relapse (Hazard Ratio [HR ]= 0.996 [95% CI: 0.803, 1.236]). Post-index ARR was significantly lower with DMF in comparison to TERI (RR = 0.667 [0.486, 0.914]). The risk of relapse was also significantly lower when switching to DMF than TERI (HR = 0.679 [0.503, 0.917]). CONCLUSION In this analysis, the effectiveness profiles for those oral DMT users specifically switching from platform therapies are consistent with findings from previous research conducted among all oral DMT users, regardless of prior therapy.
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15
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Cree BA, Arnold DL, Cascione M, Fox EJ, Williams IM, Meng X, Schofield L, Tenenbaum N. Phase IV study of retention on fingolimod versus injectable multiple sclerosis therapies: a randomized clinical trial. Ther Adv Neurol Disord 2018; 11:1756286418774338. [PMID: 29844796 PMCID: PMC5964857 DOI: 10.1177/1756286418774338] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Accepted: 02/10/2018] [Indexed: 11/16/2022] Open
Abstract
OBJECTIVE In relapsing-remitting multiple sclerosis (RRMS), suboptimal adherence to injectable disease-modifying therapies (iDMTs; interferon β-1a/b, glatiramer acetate) is common, reducing their effectiveness. Patient retention on oral fingolimod and iDMTs was evaluated in PREFERMS, a randomized, parallel-group, active-controlled, open-label, 48-week study. METHODS Patients were included if they had RRMS, were aged 18-65 years and had Expanded Disability Status Scale score up to 6, enrolled at 117 US study sites, were treatment naïve or had received only one iDMT class. Patients were randomized 1:1 (fingolimod 0.5 mg/day; preselected iDMT) by interactive voice-and-web-response system without blinding, followed up quarterly, and allowed one study-approved treatment switch after 12 weeks, or earlier for efficacy or safety reasons. The primary outcome was patient retention on randomized treatment over 48 weeks. Secondary endpoints included patient-reported outcomes, brain volume loss (BVL), and cognitive function. RESULTS Analysis of 433/436 patients receiving fingolimod and 428/439 receiving iDMTs showed that patient retention rate was significantly higher with fingolimod than with iDMTs [352 (81.3%) versus 125 (29.2%); 95% confidence interval 46.4-57.8%; p < 0.0001]. The most common treatment switch was from iDMT to fingolimod for injection-related reasons. Patient satisfaction was greater and BVL less with fingolimod than with iDMTs, with no difference in cognitive function. Adverse events were consistent with established tolerability profiles for each treatment. CONCLUSIONS In RRMS, fingolimod was associated with better treatment retention, patient satisfaction and BVL outcomes than iDMTs. Patients may persist with iDMTs, but many may switch treatment if permitted. Treatment satisfaction fosters adherence, a prerequisite for optimal outcomes.
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Affiliation(s)
- Bruce A.C. Cree
- UCSF Weill Institute for Neurosciences, Department of Neurology, 675 Nelson Rising Lane, San Francisco, CA 94158, USA
| | - Douglas L. Arnold
- NeuroRx Research and Montreal Neurological Institute, Montreal, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
| | | | - Edward J. Fox
- Central Texas Neurology Consultants, Round Rock, TX, USA
| | | | - Xiangyi Meng
- Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
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16
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Coret F, Pérez-Miralles FC, Gascón F, Alcalá C, Navarré A, Bernad A, Boscá I, Escutia M, Gil-Perotin S, Casanova B. Onset of secondary progressive multiple sclerosis is not influenced by current relapsing multiple sclerosis therapies. Mult Scler J Exp Transl Clin 2018; 4:2055217318783347. [PMID: 30090637 PMCID: PMC6077906 DOI: 10.1177/2055217318783347] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 04/19/2018] [Accepted: 05/10/2018] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND Disease-modifying therapies are thought to reduce the conversion rate to secondary progressive multiple sclerosis. OBJECTIVE To explore the rate, chronology, and contributing factors of conversion to the progressive phase in treated relapsing-remitting multiple sclerosis patients. METHODS Our study included 204 patients treated for relapsing-remitting multiple sclerosis between 1995 and 2002, prospectively followed to date. Kaplan-Meier analysis was applied to estimate the time until secondary progressive multiple sclerosis conversion, and multivariate survival analysis with a Cox regression model was used to analyse prognostic factors. RESULTS Relapsing-remitting multiple sclerosis patients were continuously treated for 13 years (SD 4.5); 36.3% converted to secondary progressive multiple sclerosis at a mean age of 42.6 years (SD 10.6), a mean time of 8.2 years (SD 5.2) and an estimated mean time of 17.2 years (range 17.1-18.1). A multifocal relapse, age older than 34 years at disease onset and treatment failure independently predicted conversion to secondary progressive multiple sclerosis but did not influence the time to reach an Expanded Disability Status Scale of 6.0. CONCLUSIONS The favourable influence of disease-modifying therapies on long-term disability in relapsing-remitting multiple sclerosis is well established. However, the time to progression onset and the subsequent clinical course in treated patients seem similar to those previously reported in natural history studies. More studies are needed to clarify the effect of disease-modifying therapies once the progressive phase has been reached.
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Affiliation(s)
| | | | | | - Carmen Alcalá
- Neuroimmunology Unit, Hospital Universitari i Politècnic La Fe, Spain
| | | | - Ana Bernad
- Neuroimmunology Unit, Hospital Clínic de València, Spain
| | - Isabel Boscá
- Neuroimmunology Unit, Hospital Universitari i Politècnic La Fe, Spain
| | - Matilde Escutia
- Neuroimmunology Unit, Hospital Universitari i Politècnic La Fe, Spain
| | - Sara Gil-Perotin
- Neuroimmunology Unit, Hospital Universitari i Politècnic La Fe, Spain
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Waubant E, Giovannoni G, Hawkes C, Lublin F. Editors' Welcome. Mult Scler Relat Disord 2017; 18:A1-A2. [PMID: 29141832 DOI: 10.1016/j.msard.2017.10.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Alberti TB, Barbosa WLR, Vieira JLF, Raposo NRB, Dutra RC. (-)-β-Caryophyllene, a CB2 Receptor-Selective Phytocannabinoid, Suppresses Motor Paralysis and Neuroinflammation in a Murine Model of Multiple Sclerosis. Int J Mol Sci 2017; 18:ijms18040691. [PMID: 28368293 PMCID: PMC5412277 DOI: 10.3390/ijms18040691] [Citation(s) in RCA: 97] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Revised: 03/18/2017] [Accepted: 03/20/2017] [Indexed: 12/05/2022] Open
Abstract
(−)-β-caryophyllene (BCP), a cannabinoid receptor type 2 (CB2)-selective phytocannabinoid, has already been shown in precedent literature to exhibit both anti-inflammatory and analgesic effects in mouse models of inflammatory and neuropathic pain. Herein, we endeavored to investigate the therapeutic potential of BCP on experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). Furthermore, we sought to demonstrate some of the mechanisms that underlie the modulation BCP exerts on autoimmune activated T cells, the pro-inflammatory scenery of the central nervous system (CNS), and demyelination. Our findings demonstrate that BCP significantly ameliorates both the clinical and pathological parameters of EAE. In addition, data hereby presented indicates that mechanisms underlying BCP immunomodulatory effect seems to be linked to its ability to inhibit microglial cells, CD4+ and CD8+ T lymphocytes, as well as protein expression of pro-inflammatory cytokines. Furthermore, it diminished axonal demyelination and modulated Th1/Treg immune balance through the activation of CB2 receptor. Altogether, our study represents significant implications for clinical research and strongly supports the effectiveness of BCP as a novel molecule to target in the development of effective therapeutic agents for MS.
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MESH Headings
- Animals
- Anti-Inflammatory Agents, Non-Steroidal/pharmacology
- Cannabinoid Receptor Agonists/pharmacology
- Cytokines/metabolism
- Demyelinating Diseases/prevention & control
- Disease Models, Animal
- Encephalomyelitis, Autoimmune, Experimental/metabolism
- Encephalomyelitis, Autoimmune, Experimental/physiopathology
- Encephalomyelitis, Autoimmune, Experimental/prevention & control
- Female
- Humans
- Hyperalgesia/prevention & control
- Mice, Inbred C57BL
- Microglia/drug effects
- Microglia/metabolism
- Multiple Sclerosis/metabolism
- Multiple Sclerosis/physiopathology
- Multiple Sclerosis/prevention & control
- Neurogenic Inflammation/metabolism
- Neurogenic Inflammation/physiopathology
- Neurogenic Inflammation/prevention & control
- Paralysis/metabolism
- Paralysis/physiopathology
- Paralysis/prevention & control
- Polycyclic Sesquiterpenes
- Receptor, Cannabinoid, CB2/agonists
- Receptor, Cannabinoid, CB2/metabolism
- Sesquiterpenes/pharmacology
- T-Lymphocytes/drug effects
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
- T-Lymphocytes, Regulatory/drug effects
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- Th1 Cells/drug effects
- Th1 Cells/immunology
- Th1 Cells/metabolism
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Affiliation(s)
- Thaís Barbosa Alberti
- Laboratory of Autoimmunity and Immunopharmacology (LAIF), Department of Health Sciences, Center of Araranguá, Federal University of Santa Catarina, Araranguá 88906-072, Brazil.
| | | | | | - Nádia Rezende Barbosa Raposo
- Research and Innovation in Health Sciences (NUPICS), Federal University of Juiz de Fora, Juiz de Fora 36036-900, Brazil.
| | - Rafael Cypriano Dutra
- Laboratory of Autoimmunity and Immunopharmacology (LAIF), Department of Health Sciences, Center of Araranguá, Federal University of Santa Catarina, Araranguá 88906-072, Brazil.
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Freedman MS, Wolinsky JS, Comi G, Kappos L, Olsson TP, Miller AE, Thangavelu K, Benamor M, Truffinet P, O'Connor PW. The efficacy of teriflunomide in patients who received prior disease-modifying treatments: Subgroup analyses of the teriflunomide phase 3 TEMSO and TOWER studies. Mult Scler 2017; 24:535-539. [PMID: 28304217 PMCID: PMC5891690 DOI: 10.1177/1352458517695468] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Teriflunomide is a once-daily oral immunomodulator approved for relapsing-remitting multiple sclerosis (MS). The objective of this post hoc analysis of the phase 3, pooled TEMSO (NCT00134563) and TOWER (NCT00751881) dataset is to evaluate the effect of teriflunomide treatment on annualised relapse rate and disability worsening across patient subgroups defined according to prior disease-modifying therapy exposure. This analysis provides further supportive evidence for a consistent effect of teriflunomide across a broad range of patients with relapsing MS, including patients who have used and discontinued other disease-modifying therapies.
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Affiliation(s)
- Mark S Freedman
- University of Ottawa and The Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
| | - Jerry S Wolinsky
- Multiple Sclerosis Research Group and MRI-Analysis Center, McGovern Medical School, UTHealth, Houston, TX, USA
| | - Giancarlo Comi
- Department of Neurology, University Vita-Salute San Raffaele, Milan, Italy
| | - Ludwig Kappos
- Neurology and Department of Biomedicine, University Hospital Basel, Basel, Switzerland
| | - Tomas P Olsson
- Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
| | - Aaron E Miller
- The Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Deleu D, Mesraoua B, El Khider H, Canibano B, Melikyan G, Al Hail H, Mhjob N, Bhagat A, Ibrahim F, Hanssens Y. Optimization and stratification of multiple sclerosis treatment in fast developing economic countries: a perspective from Qatar. Curr Med Res Opin 2017; 33:439-458. [PMID: 27892723 DOI: 10.1080/03007995.2016.1261818] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
OBJECTIVE The introduction of disease-modifying therapies (DMTs) - with varying degrees of efficacy for reducing annual relapse rate and disability progression - has considerably transformed the therapeutic landscape of relapsing-remitting multiple sclerosis (RRMS). We aim to develop rational evidence-based treatment recommendations and algorithms for the management of clinically isolated syndrome (CIS) and RRMS that conform to the healthcare system in a fast-developing economic country such as Qatar. RESEARCH DESIGN AND METHODS We conducted a systematic review using a comprehensive search of MEDLINE, PubMed, and Cochrane Database of Systematic Reviews (1 January 1990 through 30 September 2016). Additional searches of the American Academy of Neurology and European Committee for Treatment and Research in Multiple Sclerosis abstracts from 2012 through 2016 were performed, in addition to searches of the Food and Drug Administration and European Medicines Agency websites to obtain relevant safety information on these DMTs. RESULTS For each of the DMTs, the mode of action, efficacy, safety and tolerability are briefly discussed. To facilitate the interpretation, the efficacy data of the pivotal phase III trials are expressed by their most clinically useful measure of therapeutic efficacy, the number needed to treat (NNT). In addition, an overview of head-to-head trials in RRMS is provided as well as a summary of the several different RRMS management strategies (lateral switching, escalation, induction, maintenance and combination therapy) and the potential role of each DMT. Finally, algorithms were developed for CIS, active and highly active or rapidly evolving RRMS and subsequent breakthrough disease or suboptimal treatment response while on DMTs. The benefit-to-risk profiles of the DMTs, taking into account patient preference, allowed the provision of rational and safe patient-tailored treatment algorithms. CONCLUSIONS Recommendations and algorithms for the management of CIS and RRMS have been developed relevant to the healthcare system of this fast-developing economic country.
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Affiliation(s)
- Dirk Deleu
- a Department of Neurology , Neuroscience Institute, Hamad Medical Corporation , Doha , State of Qatar
| | - Boulenouar Mesraoua
- a Department of Neurology , Neuroscience Institute, Hamad Medical Corporation , Doha , State of Qatar
| | - Hisham El Khider
- a Department of Neurology , Neuroscience Institute, Hamad Medical Corporation , Doha , State of Qatar
| | - Beatriz Canibano
- a Department of Neurology , Neuroscience Institute, Hamad Medical Corporation , Doha , State of Qatar
| | - Gayane Melikyan
- a Department of Neurology , Neuroscience Institute, Hamad Medical Corporation , Doha , State of Qatar
| | - Hassan Al Hail
- a Department of Neurology , Neuroscience Institute, Hamad Medical Corporation , Doha , State of Qatar
| | - Noha Mhjob
- a Department of Neurology , Neuroscience Institute, Hamad Medical Corporation , Doha , State of Qatar
| | - Anjushri Bhagat
- a Department of Neurology , Neuroscience Institute, Hamad Medical Corporation , Doha , State of Qatar
| | - Faiza Ibrahim
- a Department of Neurology , Neuroscience Institute, Hamad Medical Corporation , Doha , State of Qatar
| | - Yolande Hanssens
- b Department of Clinical Services Unit , Pharmacy, Hamad Medical Corporation , Doha , State of Qatar
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21
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Consensus statement on the treatment of multiple sclerosis by the Spanish Society of Neurology in 2016. NEUROLOGÍA (ENGLISH EDITION) 2017. [DOI: 10.1016/j.nrleng.2016.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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Lee A, Pike J, Edwards MR, Petrillo J, Waller J, Jones E. Quantifying the Benefits of Dimethyl Fumarate Over β Interferon and Glatiramer Acetate Therapies on Work Productivity Outcomes in MS Patients. Neurol Ther 2017; 6:79-90. [PMID: 28093681 PMCID: PMC5447554 DOI: 10.1007/s40120-016-0061-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Indexed: 01/01/2023] Open
Abstract
Introduction Dimethyl fumarate (DMF) is a novel oral therapy used for the treatment of relapse-remitting multiple sclerosis (RRMS). In two 2-year pivotal Phase 3 trials in patients with RRMS, DMF significantly reduced disease activity based on both clinical and magnetic resonance imaging (MRI) findings and demonstrated an acceptable safety profile. However, there is currently a lack of comparative data which explore the relationship between work productivity and health-related quality of life (HRQoL) outcomes in RRMS and how these differ among RRMS therapies, including DMF. Methods We explored this relationship through patient-reported data from the EuroQol Five-Dimensions (EQ-5D) tool, Work Productivity and Activity Impairment Questionnaire (WPAI), and the Hamburg Quality of Life Questionnaire in Multiple Sclerosis (HAQUAMS) using the Adelphi MS DSP® dataset. Results Our data demonstrated that patients receiving DMF experienced better outcomes, relative to patients receiving beta (β)interferons or glatiramer acetate, in all WPAI subscales [overall; average treatment effect (ATE) −13.92, 95% confidence interval (CI) −18.87 to −7.08; p < 0.001], EQ-5D (ATE +0.075, 95% Cl 0.014–0.136; p = 0.016) and HAQUAMS [ATE −0.45, 95% Cl −0.61 to −0.29; p < 0.001]. The EQ-5D and HAQUAMS were used with WPAI to determine the relationship between HRQoL outcomes and work productivity. Multiple linear regression analyses were performed, adjusting for age, sex, body mass index, ethnicity and number of comorbid conditions. Conclusions These data demonstrate that therapy with DMF was associated with increased work productivity and HRQoL for patients with RRMS and that these outcomes were consistently improved compared to outcomes with interferon and glatiramer acetate therapies.
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Affiliation(s)
- Andrew Lee
- Biogen, 225 Binney Street, Cambridge, MA, USA
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23
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Tsivgoulis G, Katsanos AH, Mavridis D, Grigoriadis N, Dardiotis E, Heliopoulos I, Papathanasopoulos P, Karapanayiotides T, Kilidireas C, Hadjigeorgiou GM, Voumvourakis K, HELANI (Hellenic Academy of Neuroimmunology). The Efficacy of Natalizumab versus Fingolimod for Patients with Relapsing-Remitting Multiple Sclerosis: A Systematic Review, Indirect Evidence from Randomized Placebo-Controlled Trials and Meta-Analysis of Observational Head-to-Head Trials. PLoS One 2016; 11:e0163296. [PMID: 27684943 PMCID: PMC5042498 DOI: 10.1371/journal.pone.0163296] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Accepted: 09/05/2016] [Indexed: 12/14/2022] Open
Abstract
Background Although Fingolimod (FGD) and Natalizumab (NTZ) appear to be effective in relapsing-remitting multiple sclerosis (RRMS), they have never been directly compared in a randomized clinical trial (RCT). Methods and Findings We evaluated the comparative efficacy of FGD vs. NTZ using a meta-analytical approach. Data from placebo-controlled RCTs was used for indirect comparisons and observational data was utilized for head-to-head comparisons. We identified 3 RCTs (2498 patients) and 5 observational studies (2576 patients). NTZ was associated with a greater reduction in the 2-year annualized relapse rate (ARR; SMDindirect = -0.24;95% CI: from -0.44 to -0.04; p = 0.005) and with the probability of no disease activity at 2 years (ORindirect:1.82, 95% CI: from 1.05 to 3.15) compared to FGD, while no differences between the two therapies were found in the proportion of patients who remained relapse-free (ORindirect = 1.20;95% CI: from 0.84 to 1.71) and those with disability progression (ORindirect = 0.76;95% CI: from 0.48 to 1.21) at 2 years. In the analysis of observational data, we found no significant differences between NTZ and FGD in the 2-year ARR (SMD = -0.05; 95% CI: from -0.26 to 0.16), and 2-year disability progression (OR:1.08;95% CI: from 0.77 to 1.52). However, NTZ-treated patients were more likely to remain relapse-free at 2-years compared to FGD (OR: 2.19;95% CI: from 1.15 to 4.18; p = z0.020). Conclusions Indirect analyses of RCT data and head-to-head comparisons of observational findings indicate that NTZ may be more effective than FGD in terms of disease activity reduction in patients with RRMS. However, head-to-head RCTs are required to independently confirm this preliminary observation.
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Affiliation(s)
- Georgios Tsivgoulis
- Second Department of Neurology, “Attikon” Hospital, School of Medicine, University of Athens, Athens, Greece
- Department of Neurology, The University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
- International Clinical Research Center, Department of Neurology, St. Anne’s University Hospital in Brno, Brno, Czech Republic
- * E-mail:
| | - Aristeidis H. Katsanos
- Second Department of Neurology, “Attikon” Hospital, School of Medicine, University of Athens, Athens, Greece
- Department of Neurology, School of Medicine, University of Ioannina, Ioannina, Greece
| | - Dimitris Mavridis
- Department of Primary Education, University of Ioannina, Ioannina, Greece
- Department of Hygiene and Epidemiology, School of Medicine, University of Ioannina, Ioannina, Greece
| | - Nikolaos Grigoriadis
- Second Department of Neurology, “AHEPA” University Hospital, Aristotelion University of Thessaloniki, Thessaloniki, Macedonia, Greece
| | - Efthymios Dardiotis
- Department of Neurology, University Hospital of Larissa, University of Thessaly, Larissa, Greece
| | - Ioannis Heliopoulos
- Department of Neurology, Alexandroupolis University Hospital, Democritus University of Thrace, Alexandroupolis, Greece
| | | | - Theodoros Karapanayiotides
- Second Department of Neurology, “AHEPA” University Hospital, Aristotelion University of Thessaloniki, Thessaloniki, Macedonia, Greece
| | - Constantinos Kilidireas
- First Department of Neurology, “Eginition” Hospital, School of Medicine, University of Athens, Athens, Greece
| | | | - Konstantinos Voumvourakis
- Second Department of Neurology, “Attikon” Hospital, School of Medicine, University of Athens, Athens, Greece
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Conway DS, Thompson NR, Cohen JA. Lack of magnetic resonance imaging lesion activity as a treatment target in multiple sclerosis: An evaluation using electronically collected outcomes. Mult Scler Relat Disord 2016; 9:129-34. [PMID: 27645360 DOI: 10.1016/j.msard.2016.07.017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Revised: 07/21/2016] [Accepted: 07/26/2016] [Indexed: 11/16/2022]
Abstract
BACKGROUND The appropriate treatment target in multiple sclerosis (MS) is unclear. Lack of magnetic resonance imaging (MRI) lesion activity, a component of the no evidence of disease activity concept, has been proposed as a treatment target in MS. We used our MS database to investigate whether aggressively pursuing MRI stability by changing disease modifying therapy (DMT) when MRI activity is observed leads to better clinical and imaging outcomes. METHODS The Knowledge Program (KP) is a database linked to our electronic medical record allowing capture of patient and clinician reported outcomes. Through KP query and chart review, we identified all relapsing-remitting MS patients visiting between 1 January 2008 and 31 December 2014 with active MRIs despite DMT. Propensity modeling based on demographic and disease characteristics was used to match DMT switchers to non-switchers. KP and MRI outcomes were compared 18 months after the active MRI using mixed-effects linear regression models. RESULTS We identified 417 patients who met criteria for our analysis. After propensity matching, 78 switchers and 91 non-switchers were analyzed. There was no difference in clinical or radiologic outcomes between these groups at 18 months. CONCLUSIONS We did not find a short-term benefit of changing DMT to pursue MRI stability.
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Affiliation(s)
- Devon S Conway
- Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic Foundatio, 9500 Euclid Avenue/U10, Cleveland, OH, 44195 USA.
| | - Nicolas R Thompson
- Department of Quantitative Health Sciences, Neurological Institute Center for Outcomes Research and Evaluation, Cleveland Clinic Foundation, 9500 Euclid Avenue/JJ3, Cleveland, OH, 44195 USA
| | - Jeffrey A Cohen
- Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic Foundatio, 9500 Euclid Avenue/U10, Cleveland, OH, 44195 USA
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Calkwood J, Vollmer T, Fox RJ, Zhang R, Novas M, Sheikh SI, Viglietta V. Safety and Tolerability of Delayed-Release Dimethyl Fumarate Administered with Interferon Beta or Glatiramer Acetate in Relapsing-Remitting Multiple Sclerosis. Int J MS Care 2016; 18:138-46. [PMID: 27252601 DOI: 10.7224/1537-2073.2015-020] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND Delayed-release dimethyl fumarate (DMF; also known as gastroresistant DMF) is indicated for relapsing multiple sclerosis (MS). The objective of this study was to explore the safety and tolerability of DMF when administered with interferon beta (IFNβ) or glatiramer acetate (GA). METHODS Patients with relapsing-remitting MS receiving established therapy with the same dose of IFNβ or GA for at least 12 months continued their prescribed therapy for 2 months (monotherapy period) and then received DMF 240 mg three times daily in addition to their prescribed MS therapy for 6 months (add-on therapy period). Safety and magnetic resonance imaging outcomes were monitored monthly. RESULTS During the add-on therapy period, in the DMF+IFNβ (n = 57) and DMF+GA (n = 47) groups, the overall incidence of adverse events was 95% and 100%, respectively; the most common adverse events were flushing, diarrhea, and abdominal pain. In both groups, mean lymphocyte counts decreased but remained within normal limits, and hepatic transaminase levels increased transiently; no case met Hy's law criteria. There was no overall increased risk of infection. In both groups, gadolinium-enhancing lesion activity and new/enlarging T2 lesions decreased compared with the monotherapy period (exploratory endpoints). CONCLUSIONS The safety profile of DMF taken with IFNβ or GA was acceptable and consistent with the known safety profile of DMF monotherapy.
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Affiliation(s)
- Jonathan Calkwood
- Schapiro Center for Multiple Sclerosis, Minneapolis Clinic of Neurology, Golden Valley, MN, USA (JC); Department of Neurology, University of Colorado School of Medicine, RMMSC at Anschutz, Aurora, CO, USA (TV); Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA (RJF); and Biogen, Cambridge, MA, USA (RZ, MN, SIS, VV)
| | - Timothy Vollmer
- Schapiro Center for Multiple Sclerosis, Minneapolis Clinic of Neurology, Golden Valley, MN, USA (JC); Department of Neurology, University of Colorado School of Medicine, RMMSC at Anschutz, Aurora, CO, USA (TV); Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA (RJF); and Biogen, Cambridge, MA, USA (RZ, MN, SIS, VV)
| | - Robert J Fox
- Schapiro Center for Multiple Sclerosis, Minneapolis Clinic of Neurology, Golden Valley, MN, USA (JC); Department of Neurology, University of Colorado School of Medicine, RMMSC at Anschutz, Aurora, CO, USA (TV); Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA (RJF); and Biogen, Cambridge, MA, USA (RZ, MN, SIS, VV)
| | - Ray Zhang
- Schapiro Center for Multiple Sclerosis, Minneapolis Clinic of Neurology, Golden Valley, MN, USA (JC); Department of Neurology, University of Colorado School of Medicine, RMMSC at Anschutz, Aurora, CO, USA (TV); Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA (RJF); and Biogen, Cambridge, MA, USA (RZ, MN, SIS, VV)
| | - Mark Novas
- Schapiro Center for Multiple Sclerosis, Minneapolis Clinic of Neurology, Golden Valley, MN, USA (JC); Department of Neurology, University of Colorado School of Medicine, RMMSC at Anschutz, Aurora, CO, USA (TV); Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA (RJF); and Biogen, Cambridge, MA, USA (RZ, MN, SIS, VV)
| | - Sarah I Sheikh
- Schapiro Center for Multiple Sclerosis, Minneapolis Clinic of Neurology, Golden Valley, MN, USA (JC); Department of Neurology, University of Colorado School of Medicine, RMMSC at Anschutz, Aurora, CO, USA (TV); Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA (RJF); and Biogen, Cambridge, MA, USA (RZ, MN, SIS, VV)
| | - Vissia Viglietta
- Schapiro Center for Multiple Sclerosis, Minneapolis Clinic of Neurology, Golden Valley, MN, USA (JC); Department of Neurology, University of Colorado School of Medicine, RMMSC at Anschutz, Aurora, CO, USA (TV); Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA (RJF); and Biogen, Cambridge, MA, USA (RZ, MN, SIS, VV)
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Gallo P, Van Wijmeersch B. Overview of the management of relapsing-remitting multiple sclerosis and practical recommendations. Eur J Neurol 2016; 22 Suppl 2:14-21. [PMID: 26374509 DOI: 10.1111/ene.12799] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Accepted: 06/05/2015] [Indexed: 11/29/2022]
Abstract
The initial phases of the clinical course of relapsing-remitting multiple sclerosis (MS) are characterized by a mainly inflammatory pathology which gives way to a largely neurodegenerative process as the disease evolves. As all currently available disease-modifying therapies aim to control inflammation, the window of opportunity for use is early in the disease course, specifically at the time of a clinically isolated syndrome suggestive of MS or in the early stages of relapsing-remitting MS. Approximately 30% of patients treated with first-line immunomodulators (interferon-β or glatiramer acetate) show a suboptimal response during the first 1-2 years and require a switch to an alternative therapy. It is recommended not to wait too long to switch in order to prevent disease progression. Patients with a poor prognosis in particular may require a timely switch to a second-line agent. Regular monitoring of disease and therapy in patients with MS is essential. In the first year after diagnosis, clinical evaluations (neurological status, symptomatic assessment, patient well-being) should be performed at baseline, 3, 6 and 12 months, and then every 6 months thereafter. Brain magnetic resonance imaging (MRI) should be performed every 6 months in the first year of treatment, and at least once yearly thereafter. A spinal cord MRI should be performed once yearly in patients presenting spinal symptoms.
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Affiliation(s)
- P Gallo
- Department of Neurosciences, Multiple Sclerosis Centre - Veneto Region (CeSMuV), University Hospital of Padova, Padova, Italy
| | - B Van Wijmeersch
- Rehabilitation and MS-Centre Overpelt and Biomedical Institute, University Hasselt, Hasselt, Belgium
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García Merino A, Ramón Ara Callizo J, Fernández Fernández O, Landete Pascual L, Moral Torres E, Rodríguez-Antigüedad Zarrantz A. Consensus statement on the treatment of multiple sclerosis by the Spanish Society of Neurology in 2016. Neurologia 2016; 32:113-119. [PMID: 27157522 DOI: 10.1016/j.nrl.2016.02.026] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 02/27/2016] [Indexed: 10/21/2022] Open
Abstract
With the advent of new disease-modifying drugs, the treatment of multiple sclerosis is becoming increasingly complex. Using consensus statements is therefore advisable. The present consensus statement, which was drawn up by the Spanish Society of Neurology's study group for demyelinating diseases, updates previous consensus statements on the disease. The present study lists the medications currently approved for multiple sclerosis and their official indications, and analyses such treatment-related aspects as activity, early treatment, maintenance, follow-up, treatment failure, changes in medication, and special therapeutic situations. This consensus statement includes treatment recommendations for a wide range of demyelinating diseases, from isolated demyelinating syndromes to the different forms of multiple sclerosis, as well as recommendations for initial therapy and changes in drug medication, and additional comments on induction and combined therapy and practical aspects of the use of these drugs.
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Affiliation(s)
| | | | | | | | - E Moral Torres
- Hospital Moisés Broggi, Sant Joan Despí, Barcelona, España
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28
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Junqueira SC, dos Santos Coelho I, Lieberknecht V, Cunha MP, Calixto JB, Rodrigues ALS, Santos ARS, Dutra RC. Inosine, an Endogenous Purine Nucleoside, Suppresses Immune Responses and Protects Mice from Experimental Autoimmune Encephalomyelitis: a Role for A2A Adenosine Receptor. Mol Neurobiol 2016; 54:3271-3285. [DOI: 10.1007/s12035-016-9893-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Accepted: 04/17/2016] [Indexed: 11/30/2022]
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Ziemssen T, Derfuss T, de Stefano N, Giovannoni G, Palavra F, Tomic D, Vollmer T, Schippling S. Optimizing treatment success in multiple sclerosis. J Neurol 2015; 263:1053-65. [PMID: 26705122 PMCID: PMC4893374 DOI: 10.1007/s00415-015-7986-y] [Citation(s) in RCA: 139] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2015] [Accepted: 11/25/2015] [Indexed: 01/01/2023]
Abstract
Despite important advances in the treatment of multiple sclerosis (MS) over recent years, the introduction of several disease-modifying therapies (DMTs), the burden of progressive disability and premature mortality associated with the condition remains substantial. This burden, together with the high healthcare and societal costs associated with MS, creates a compelling case for early treatment optimization with highly efficacious therapies. Often, patients receive several first-line therapies, while more recent and in part more effective treatments are still being introduced only after these have failed. However, with the availability of highly efficacious therapies, a novel treatment strategy has emerged, where the aim is to achieve no evidence of disease activity (NEDA). Achieving NEDA necessitates regular monitoring of relapses, disability and functionality. However, there is only a poor correlation between conventional magnetic resonance imaging measures like T2 hyperintense lesion burden and the level of clinical disability. Hence, MRI-based measures of brain atrophy have emerged in recent years potentially reflecting the magnitude of MS-related neuroaxonal damage. Currently available DMTs differ markedly in their effects on brain atrophy: some, such as fingolimod, have been shown to significantly slow brain volume loss, compared to placebo, whereas others have shown either no, inconsistent, or delayed effects. In addition to regular monitoring, treatment optimization also requires early intervention with efficacious therapies, because accumulating evidence shows that effective intervention during a limited period early in the course of MS is critical for maintaining neurological function and preventing subsequent disability. Together, the advent of new MS therapies and evolving management strategies offer exciting new opportunities to optimize treatment outcomes.
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Affiliation(s)
- Tjalf Ziemssen
- MS Center Dresden, Center of Clinical Neuroscience, Neurological Clinic, University Hospital Carl Gustav Carus, Dresden University of Technology, Fetscherstrasse 74, 01307, Dresden, Germany.
| | - Tobias Derfuss
- MS Center Dresden, Center of Clinical Neuroscience, Neurological Clinic, University Hospital Carl Gustav Carus, Dresden University of Technology, Fetscherstrasse 74, 01307, Dresden, Germany
| | - Nicola de Stefano
- Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy
| | - Gavin Giovannoni
- Queen Mary University London, Barts and The London School of Medicine and Dentistry, London, UK
| | - Filipe Palavra
- Neurology-Neuroimmunology Department, Multiple Sclerosis Centre of Catalonia (Cemcat), Vall d'Hebron University Hospital, Barcelona, Spain
| | | | - Tim Vollmer
- University of Colorado Health Sciences Center, Aurora, CO, USA
| | - Sven Schippling
- Department of Neurology, Neuroimmunology and Multiple Sclerosis Research, University Hospital Zurich, University of Zurich, Zurich, Switzerland
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Freedman MS, Wolinsky JS, Truffinet P, Comi G, Kappos L, Miller AE, Olsson TP, Benamor M, Chambers S, O'Connor PW. A randomized trial of teriflunomide added to glatiramer acetate in relapsing multiple sclerosis. Mult Scler J Exp Transl Clin 2015; 1:2055217315618687. [PMID: 28607708 PMCID: PMC5433345 DOI: 10.1177/2055217315618687] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Background Teriflunomide is a once-daily oral immunomodulator for the treatment of relapsing−remitting MS. Objective To evaluate the safety and tolerability of teriflunomide as add-on therapy to a stable dose of glatiramer acetate (GA) in patients with relapsing forms of MS (RMS). Methods Phase II, randomized, double-blind, add-on, placebo-controlled study. The primary objective was to assess safety and tolerability; secondary objectives were to evaluate effects of treatment on disease activity assessed by MRI and relapse. Results Patients with RMS on GA (N = 123) were randomized 1:1:1 to receive teriflunomide 14 mg (n = 40), 7 mg (n = 42), or placebo (n = 41) for 24 weeks; 96 patients entered the 24-week extension, remaining on original treatment allocation. Teriflunomide was well tolerated over 48 weeks. The frequency of adverse events (AEs) was low across all groups; 5 (12.2%), 3 (7.1%), and 2 (5.0%) patients in the 14 mg, 7 mg, and placebo groups, respectively, discontinued treatment due to AEs. Teriflunomide reduced the number of T1-Gd lesions vs placebo (14 mg: 46.6% relative reduction, p = 0.1931; 7 mg: 64.0%: relative reduction, p = 0.0306). Conclusions Teriflunomide added to stable-dose GA had acceptable safety and tolerability, and reduced some MRI markers of disease activity compared with GA alone. NCT00475865 (core study); NCT00811395 (extension).
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Affiliation(s)
- M S Freedman
- University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, Canada
| | - J S Wolinsky
- University of Texas Health Science Center at Houston, Houston, TX, USA
| | - P Truffinet
- Genzyme, a Sanofi company, Chilly-Mazarin, France
| | - G Comi
- University Vita-Salute San Raffaele, Milan, Italy
| | - L Kappos
- University Hospital Basel, Basel, Switzerland
| | - A E Miller
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | | | - S Chambers
- Fishawack Communications Ltd, Abingdon, UK
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Ziemssen T, Gilgun-Sherki Y. Sub-analysis of geographical variations in the 2-year observational COPTIMIZE trial of patients with relapsing-remitting multiple sclerosis converting to glatiramer acetate. BMC Neurol 2015; 15:189. [PMID: 26450155 PMCID: PMC4599648 DOI: 10.1186/s12883-015-0448-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Accepted: 09/29/2015] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Studies suggest that patients with relapsing-remitting multiple sclerosis (RRMS) who fail to benefit from a disease-modifying treatment (DMT) may benefit from converting to another DMT class. COPTIMIZE was a 24-month observational study designed to assess the disease course of patients converting to glatiramer acetate (GA) 20 mg daily from another DMT and the association of disease characteristics and reasons for converting. This sub-analysis was to determine if any findings varied by three geographic locations: Latin America (LA), Canada and Western Europe (CWE), and Eastern Europe (EE). METHODS A total of 668 patients were included (263 LA, 248 CWE, 157 EE) in an analysis of annualized relapse rate (ARR) and annualized rate of deterioration (ARD), as well as secondary endpoints including reason for DMT switch and changes in disability and fatigue scores. Repeated-measures analysis of variance and log transformation were used to analyze ARR and ARD, whereas the Wilcoxon signed rank test was used for secondary endpoints. RESULTS The sub-analysis of treatment outcomes stratified by region showed that Latin American patients had higher ARR before conversion to GA compared with patients from the other two areas and subsequently experienced the largest reduction in ARR. Latin American patients also had higher baseline rates of comorbidities and relapses with incomplete remissions and improved more than those in the other two regions based on measures of fatigue, quality of life, depression, and cognition scores. Latin American patients also generally had a better perception of the benefits associated with their conversion to GA in terms of efficacy and adverse events. CONCLUSIONS These findings indicate that, in RRMS patients, converting to GA is associated with positive treatment outcomes regardless of geographic location. However, the reasons for converting and the type and degree of any associated benefits appear to vary depending on various factors, including patients' geographical location.
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Affiliation(s)
- Tjalf Ziemssen
- Center of Clinical Neuroscience, Neurological University Clinic, University Clinic Carl Gustav Carus, University of Technology Dresden, Fetscherstraße 74, D-01307, Dresden, Germany.
| | - Yossi Gilgun-Sherki
- Teva Pharmaceutical Industries Ltd, 5 Basel Street, Petah Tikva, 49131, Israel.
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Ziemssen T, De Stefano N, Sormani MP, Van Wijmeersch B, Wiendl H, Kieseier BC. Optimizing therapy early in multiple sclerosis: An evidence-based view. Mult Scler Relat Disord 2015; 4:460-469. [DOI: 10.1016/j.msard.2015.07.007] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Revised: 06/01/2015] [Accepted: 07/15/2015] [Indexed: 01/26/2023]
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Fernández-Fournier M, Tallón-Barranco A, Chamorro B, Martínez-Sánchez P, Puertas I. Differential glatiramer acetate treatment persistence in treatment-naive patients compared to patients previously treated with interferon. BMC Neurol 2015; 15:141. [PMID: 26286576 PMCID: PMC4545781 DOI: 10.1186/s12883-015-0399-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 08/05/2015] [Indexed: 11/10/2022] Open
Abstract
Background In the treatment of multiple sclerosis, a change of therapy is considered after treatment failure or adverse events. Although disease modifying drugs’ (DMD) efficacy and side effects have been fully analysed in clinical trials, the effects of previous therapy use are less well studied. We aimed to study medication persistence with glatiramer acetate in treatment-naive patients and in patients previously treated with interferon. Methods A retrospective study of relapsing-remitting multiple sclerosis patients treated with glatiramer acetate in an MS Unit of a Spanish University Hospital (January 2004 – September 2013). Treatment time on glatiramer acetate was studied. Reasons for treatment discontinuation were considered as follows: lack of efficacy, serious adverse event, injection-related side effect, pregnancy and lost to follow-up. Use of prior DMD was registered and analysed. Homogeneity of groups was analysed using Fisher's and Mann-Whitney’s tests. The Kaplan Meier method and Cox regression model were used to estimate time to and risk of treatment discontinuation. Results In total, 155 relapsing-remitting multiple sclerosis patients were treated with glatiramer acetate: 100 treatment-naive patients and 55 treated previously with interferon. At the end of the study, 76 patients (49.0 %) continued on glatiramer acetate (with an average treatment time (ATT) of 50.4 months, s.d.32.8) and 50 patients (32.3 %) had switched therapy: 27 patients (17.4 %) for inefficacy (ATT 29.2 months, s.d.17.5), 20 patients (12.9 %) for injection site reactions (ATT 16.5 months, s.d.20.3) and 3 patients (1.9 %) after serious adverse events (ATT 15.7 months, s.d.15.1). ATT in our cohort was 39 months (s.d.30.0), median follow-up 34 months. Six months after glatiramer acetate initiation, probability of persisting on GA was 91.4 %, 82.5 % after 12 months and 72.5 % after 2 years. The risk of glatiramer acetate treatment discontinuation was 2.8 [1.7 – 4.8] times greater for treatment-naive patients than for patients treated previously with interferon and this was hardly modified after adjusting for sex and age. Conclusions Glatiramer acetate was safe and useful with low rates of serious adverse events and low rates of break-through disease. Injection intolerance proved a major limitation to glatiramer acetate use. Patients who had been previously treated with interferons presented a lower probability of glatiramer acetate discontinuation than treatment-naive patients.
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Affiliation(s)
| | - Antonio Tallón-Barranco
- Clinical Neuroimmunology and Multiple Sclerosis Unit, La Paz University Hospital, Madrid, Spain.
| | - Beatriz Chamorro
- Clinical Neuroimmunology and Multiple Sclerosis Unit, La Paz University Hospital, Madrid, Spain.
| | | | - Inmaculada Puertas
- Clinical Neuroimmunology and Multiple Sclerosis Unit, La Paz University Hospital, Madrid, Spain.
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Gajofatto A, Benedetti MD. Treatment strategies for multiple sclerosis: When to start, when to change, when to stop? World J Clin Cases 2015; 3:545-555. [PMID: 26244148 PMCID: PMC4517331 DOI: 10.12998/wjcc.v3.i7.545] [Citation(s) in RCA: 183] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Revised: 03/02/2015] [Accepted: 05/06/2015] [Indexed: 02/05/2023] Open
Abstract
Multiple sclerosis (MS) is a chronic inflammatory condition of the central nervous system determined by a presumed autoimmune process mainly directed against myelin components but also involving axons and neurons. Acute demyelination shows as clinical relapses that may fully or partially resolve, while chronic demyelination and neuroaxonal injury lead to persistent and irreversible neurological symptoms, often progressing over time. Currently approved disease-modifying therapies are immunomodulatory or immunosuppressive drugs that significantly although variably reduce the frequency of attacks of the relapsing forms of the disease. However, they have limited efficacy in preventing the transition to the progressive phase of MS and are of no benefit after it has started. It is therefore likely that the potential advantage of a given treatment is condensed in a relatively limited window of opportunity for each patient, depending on individual characteristics and disease stage, most frequently but not necessarily in the early phase of the disease. In addition, a sizable proportion of patients with MS may have a very mild clinical course not requiring a disease-modifying therapy. Finally, individual response to existing therapies for MS varies significantly across subjects and the risk of serious adverse events remains an issue, particularly for the newest agents. The present review is aimed at critically describing current treatment strategies for MS with a particular focus on the decision of starting, switching and stopping commercially available immunomodulatory and immunosuppressive therapies.
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Tanaka M. [Natalizumab treatment in multiple sclerosis]. Rinsho Shinkeigaku 2015; 55:537-43. [PMID: 26156254 DOI: 10.5692/clinicalneurol.cn-000690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Multiple sclerosis is a neurodegenerative and inflammatory immune disorder in the central nervous system (CNS). Most patients show relapse-remitting clinical course. Some disease modifying medications for preventing the relapses including natalizumab (NTZ) are approved in Japan. Natalizumab (NTZ), a monoclonal antibody against α4 integrin present on the surface of lymphocytes, inhibits the binding of lymphocytes to vascular cell adhesion molecule-1 (VCAM-1) of endothelial cells and blocks the penetration of encephalitogenic T cells into the CNS. This review provides an update on the efficacy of an inhibition of relapses, adverse effects including progressive multifocal leukoencephalopathy, treatment after NTZ discontinuation, and body weight based treatment.
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Affiliation(s)
- Masami Tanaka
- Multiple Sclerosis Center, National Hospital Organization, Utano National Hospital
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Interferon Beta-1a (AVONEX®) as a Treatment Option for Untreated Patients with Multiple Sclerosis (AXIOM): A Prospective, Observational Study. Int J Mol Sci 2015; 16:15271-86. [PMID: 26154767 PMCID: PMC4519899 DOI: 10.3390/ijms160715271] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2015] [Revised: 05/26/2015] [Accepted: 05/27/2015] [Indexed: 11/25/2022] Open
Abstract
The efficacy and safety of first-line disease-modifying therapies (DMT) for relapsing-remitting multiple sclerosis (RRMS) has been demonstrated in pivotal, randomized trials, but these studies do not reflect the routine care setting where treatment gaps or switches are common. The Avonex as Treatment Option for Untreated MS Patients (AXIOM) trial assessed the efficacy of newly-initiated intramuscular interferon beta-1a (IM IFNb-1a) after a treatment-free interval, with particular consideration of the previous course of disease and therapy. The AXIOM trial was an open, 12-month, observational, non-interventional study with a retrospective and a prospective part conducted in Germany. RRMS patients with a treatment-free interval of at least three months were included and treated with IFNb-1a for up to 12 months. Relapse rate, disability progression, injection-related parameters and quality of life observed during the prospective part were compared with retrospectively-collected data. Two hundred and thirty five RRMS patients participated in AXIOM. The mean relapse rate decreased from 1.1 in the three months before baseline to 0.2 per quarter during the twelve-month observational period; the Multiple Sclerosis Functional Composite score improved during twelve months of IM IFNb-1a treatment, while the Expanded Disability Status Scale score did not change over the course of this study. Compared to previous DMTs (IM IFNb-1a, subcutaneous IFNb-1a (SC IFNb-1a), SC IFNb-1b, glatiramer acetate), the patients experienced less injection site reactions and flu-like symptoms, with a stated improved quality of life. IM IFNb-1a was effective and well accepted in RRMS patients with no or discontinued previous therapy. These results from the routine care setting may inform optimization of DMT treatment in RRMS, but need confirmation in further studies.
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Khachanova NV, Davydovskaya MV. [Criteria of ineffectiveness of treatment with first-line therapy: how to use MRI results in decision making?]. Zh Nevrol Psikhiatr Im S S Korsakova 2015; 115:75-78. [PMID: 26081342 DOI: 10.17116/jnevro20151152275-78] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The importance of MRI stuides in the control over treatment efficacy in multiple sclerosis and appropriate recommendations on drug substitution during treatment are discussed. We suggest low, middle or high risk in respect to the efficacy of current treatment. Accordingly, drug substitution can be related with the low level of fears for all three criteria or the moderate level for any two criteria or the high level for any one criterion. Since MRI criteria are important, this model appears to be the most rational because the physician can make a decision about treatment escalation if the patient has ≥3 new T2-lesions or ≥3 contrast-enhanced T1-lesions.
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Affiliation(s)
- N V Khachanova
- Pirogov Russian National Research Medical University, Moscow
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The Transition From First-Line to Second-Line Therapy in Multiple Sclerosis. Curr Treat Options Neurol 2015; 17:354. [DOI: 10.1007/s11940-015-0354-5] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Update on treatments in multiple sclerosis. Presse Med 2015; 44:e137-51. [DOI: 10.1016/j.lpm.2015.02.008] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2014] [Revised: 02/01/2015] [Accepted: 02/09/2015] [Indexed: 02/04/2023] Open
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McQueen RB, Livingston T, Vollmer T, Corboy J, Buckley B, Allen RR, Nair K, Campbell JD. Increased relapse activity for multiple sclerosis natalizumab users who become nonpersistent: a retrospective study. J Manag Care Spec Pharm 2015; 21:210-8b. [PMID: 25726030 PMCID: PMC10397756 DOI: 10.18553/jmcp.2015.21.3.210] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Natalizumab disease-modifying therapy for relapsing-remitting multiple sclerosis (MS) is efficacious in randomized controlled trials. Few studies have estimated the association between real-world natalizumab persistence behavior and relapse-related outcomes. OBJECTIVES To (a) examine the impact of using natalizumab consistently (i.e., persistent) on relapse-related outcomes as compared with transitioning to inconsistent natalizumab use (i.e., nonpersistent) and (b) examine the impact of other treatment patterns on relapse-related outcomes for those who initiated natalizumab. METHODS Using the IMS PharMetrics Plus claims database (years 2006-2012), we identified MS subjects who initiated natalizumab (no natalizumab claims in year prior) and had at least 2 years of follow-up. Persistence in annual follow-up periods was defined as no 90-day or greater gap in natalizumab therapy. Relapse was an MS-related hospitalization or outpatient visit with intravenous or oral steroid burst claim within 7 days. Analyses compared observations based on changes in natalizumab persistence and natalizumab nonpersistence status from 1 year to the next (e.g., transitioning from persistent to nonpersistent), estimating differences in mean annual relapses and mean annual relapse-related costs. RESULTS A total of 2,407 natalizumab initiators had at least 2 years of follow-up, yielding 4,770 year-to-year natalizumab treatment patterns where each subject contributed 1, 2, or 3 year-to-year treatment patterns. In the year prior, 3,187 treatment patterns were persistent; 731 (22.9%) of these transitioned to nonpersistence. The remaining 1,583 treatment patterns were nonpersistent in the year prior; 132 (8.3%) of these transitioned to persistence. Persistent to nonpersistent treatment patterns were associated with a mean relapse-rate increase of 0.23 (95% CI = 0.12, 0.35), and a mean increase in relapse-related costs of $1,346 (95% CI = $97, $2,595). Nonpersistent to persistent treatment patterns were associated with a mean relapse-rate decrease of -0.15 (95% CI = -0.32, 0.017) and a mean decrease in relapse-related costs of -$1,369 (95% CI = -$2,761, $23). CONCLUSIONS Findings suggest that real-world persistent natalizumab users who become nonpersistent have statistically significant increases in annual relapses and relapse-related costs. Those who transition from nonpersistent to persistent have nonsignificant reductions in relapses and their associated costs.
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Affiliation(s)
- R Brett McQueen
- University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Anschutz Medical Campus, Mail Stop C238, 12850 E. Montview Blvd., Aurora, CO 80045. Tel.: 303.709.9264; FAX: 303.724.0979.
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Spelman T, Kalincik T, Zhang A, Pellegrini F, Wiendl H, Kappos L, Tsvetkova L, Belachew S, Hyde R, Verheul F, Grand-Maison F, Izquierdo G, Grammond P, Duquette P, Lugaresi A, Lechner-Scott J, Oreja-Guevara C, Hupperts R, Petersen T, Barnett M, Trojano M, Butzkueven H. Comparative efficacy of switching to natalizumab in active multiple sclerosis. Ann Clin Transl Neurol 2015; 2:373-87. [PMID: 25909083 PMCID: PMC4402083 DOI: 10.1002/acn3.180] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Revised: 12/09/2014] [Accepted: 01/08/2015] [Indexed: 12/29/2022] Open
Abstract
OBJECTIVE To compare treatment efficacy and persistence in patients who switched to natalizumab versus those who switched between glatiramer acetate (GA) and interferon-beta (IFNβ) after an on-treatment relapse on IFNβ or GA using propensity score matched real-world datasets. METHODS Patients included were registered in MSBase or the TYSABRI Observational Program (TOP), had relapsed on IFNβ or GA within 12 months prior to switching to another therapy, and had initiated natalizumab or IFNβ/GA treatment ≤6 months after discontinuing prior therapy. Covariates were balanced across post switch treatment groups by propensity score matching at treatment initiation. Relapse, persistence, and disability measures were compared between matched treatment arms in the total population (n = 869/group) and in subgroups defined by prior treatment history (IFNβ only [n = 578/group], GA only [n = 165/group], or both IFNβ and GA [n = 176/group]). RESULTS Compared to switching between IFNβ and GA, switching to natalizumab reduced annualized relapse rate in year one by 65-75%, the risk of first relapse by 53-82% (mean follow-up 1.7-2.2 years) and treatment discontinuation events by 48-65% (all P ≤ 0.001). In the total population, switching to natalizumab reduced the risk of confirmed disability progression by 26% (P = 0.036) and decreased the total disability burden by 1.54 EDSS-years (P < 0.0001) over the first 24 months post switch. INTERPRETATION Using large, real-world, propensity-matched datasets we demonstrate that after a relapse on IFNβ or GA, switching to natalizumab (rather than between IFNβ and GA) led to superior outcomes for patients in all measures assessed. Results were consistent regardless of the prior treatment identity.
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Affiliation(s)
- Timothy Spelman
- Department of Medicine and Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne Melbourne, Australia
| | - Tomas Kalincik
- Department of Medicine and Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne Melbourne, Australia
| | | | - Fabio Pellegrini
- Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari Bari, Italy
| | - Heinz Wiendl
- Department of Neurology, University of Münster Münster, Germany
| | - Ludwig Kappos
- Department of Neurology, University Hospital Basel Basel, Switzerland
| | | | | | | | | | | | | | - Pierre Grammond
- Center de réadaptation déficience physique Chaudière-Appalache Levis, Canada
| | | | - Alessandra Lugaresi
- MS Center, Department of Neuroscience, Imaging and Clinical Sciences, University "G. d'Annunzio" Chieti, Italy
| | | | | | | | | | | | - Maria Trojano
- Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari Bari, Italy
| | - Helmut Butzkueven
- Department of Medicine and Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne Melbourne, Australia ; Department of Neurology, Eastern Health, Monash University Box Hill, Australia
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Kulakova OG, Tsareva EY, Lvovs D, Favorov AV, Boyko AN, Favorova OO. Comparative pharmacogenetics of multiple sclerosis: IFN-β versus glatiramer acetate. Pharmacogenomics 2014; 15:679-85. [PMID: 24798724 DOI: 10.2217/pgs.14.26] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Various diseases require the selection of preferable treatment out of available alternatives. Multiple sclerosis (MS), an autoimmune inflammatory/neurodegenerative disease of the CNS, requires long-term medication with either specific disease-modifying therapy (DMT) - IFN-β or glatiramer acetate (GA) - which remain the only first-line DMTs in all countries. A significant share of MS patients are resistant to treatment with one or the other DMT; therefore, the earliest choice of preferable DMT is of particular importance. A number of conventional pharmacogenetic studies performed up to the present day have identified the treatment-sensitive genetic biomarkers that might be specific for the particular drug; however, the suitable biomarkers for selection of one or another first-line DMT are remained to be found. Comparative pharmacogenetic analysis may allow the identification of the discriminative genetic biomarkers, which may be more informative for an a priori DMT choice than those found in conventional pharmacogenetic studies. The search for discriminative markers of preferable first-line DMT, which differ in carriage between IFN-β responders and GA responders as well as between IFN-β nonresponders and GA nonresponders, has been performed in 253 IFN-β-treated MS patients and 285 GA-treated MS patients. A bioinformatics algorithm for identification of composite biomarkers (allelic sets) was applied on a unified set of immune-response genes, which are relevant for IFN-β and/or GA modes of action, and identical clinical criteria of treatment response. We found the range of discriminative markers, which include polymorphic variants of CCR5, IFNAR1, TGFB1, DRB1 or CTLA4 genes, in different combinations. Every allelic set includes the CCR5 genetic variant, which probably suggests its crucial role in the modulation of the DMT response. Special attention should be given to the (CCR5*d+ IFNAR1*G) discriminative combination, which clearly points towards IFN-β treatment choice for carriers of this combination. As a whole the comparative approach provides an option for the identification of prognostic composite biomarkers for a preferable medication among available alternatives.
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Affiliation(s)
- Olga G Kulakova
- Pirogov Russian National Research Medical University, Ostrovitianov str. 1, 117997, Moscow, Russia
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Abstract
Abstract:Background:Differences in Multiple sclerosis (MS) disease-modifying therapy (DMT) prescribing patterns between different groups of neurologists have not been explored.Objective:To examine concentrations of prescribing patterns and to assess if MS-specialists use a broader range of DMTs relative to general neurologists.Methods:We conducted a cross-sectional study using administrative claims databases in Ontario, Canada to link neurologists to 2009 DMT prescription data. MS specialization was defined using both practice location and prescription patterns. Lorenz curves and Gini coefficients were constructed to examine prescribing patterns, separating neurologist characteristics dichotomously and separating Avonex from the other standard DMTs (Betaseron, Rebif and Copaxone). Gini coefficient 95% confidence intervals (CIs) were derived using jack-knife statistical techniques.Results:Prescriptions were highly concentrated with 12% of Ontario neurologists prescribing 80% of DMTs. There was a trend towards Avonex being more commonly prescribed relative to the other DMTs. When MS specialization was defined by DMT prescribing, high-volume prescribing neurologists showed a broader range of DMT prescribing (Gini 0.38-0.44) in comparison to low-volume prescribers (Gini 0.57-0.66).Conclusions:The majority of DMTs are prescribed by a small subset of neurologists. High-volume prescribing MS-specialists show more variability in DMT use while low-volume prescribers tend to individually focus on a narrower range of DMTs.
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Carrithers MD. Update on disease-modifying treatments for multiple sclerosis. Clin Ther 2014; 36:1938-1945. [PMID: 25218310 DOI: 10.1016/j.clinthera.2014.08.006] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Accepted: 08/17/2014] [Indexed: 02/09/2023]
Abstract
PURPOSE The purpose of this review is to discuss the selection and use of disease- modifying treatments for patients with relapsing forms of multiple sclerosis (MS). METHODS PubMed was searched (1966-2014) using the terms multiple sclerosis, treatment, interferon, glatiramer acetate, dimethyl fumarate, fingolimod, teriflunomide, natalizumab, rituximab, and alemtuzumab. FINDINGS MS is a chronic neurological disorder that can cause a substantial degree of disability. Because of its usual onset in young adults, patients may require treatment for several decades. Currently available agents include platform injectable therapies, newer oral agents, and second-line monoclonal antibody treatments. Treatment decisions have become more complex with the introduction of new approaches, and a major goal is to balance perceived efficacy and tolerability in a specific patient with the relative impact of disease activity and adverse events on quality of life. Here the options for disease-modifying treatments for relapsing forms of MS are reviewed, and current and future challenges are discussed. IMPLICATIONS An evidence-based approach can be used for the selection of disease-modifying treatments based on disease phenotype and severity, adverse events, and perceived efficacy.
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Affiliation(s)
- Michael D Carrithers
- Neurology Service, William S. Middleton Memorial Veterans Hospital, Departments of Neurology and Pathology and Program in Cellular and Molecular Pathology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
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Sá MJ, de Sá J, Sousa L. Relapsing-remitting multiple sclerosis: patterns of response to disease-modifying therapies and associated factors: a national survey. Neurol Ther 2014; 3:89-99. [PMID: 26000225 PMCID: PMC4386429 DOI: 10.1007/s40120-014-0019-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2014] [Indexed: 11/26/2022] Open
Abstract
Introduction Current treatments for relapsing–remitting multiple sclerosis (RRMS) are only partially effective. The objective of this study was to characterize treatment response in RRMS patients in Portugal to 12-month therapy with first-line disease-modifying therapies. Methods In this retrospective study, neurologists at participating centers completed survey questionnaires using records of patients with RRMS who had received first-line treatment with one of five European Medicine Agency-approved agents in the 12 months prior to inclusion in the survey. Sub-optimal responders included patients treated for at least 1 year, and who had ≥1 relapse(s) or an increase of 1.5 points on the Expanded Disability Status Scale (EDSS; if baseline EDSS was 0) or an increase of ≥0.5 points (baseline EDSS ≥1). Optimal responders included patients treated for at least 1 year without relapse and who had an increase of <1.5 points on EDSS (if baseline EDSS was 0) or no increase in EDSS (baseline EDSS ≥1). Results Data for 1,131 patients from 15 centers were analyzed. Twenty-six percent (95% confidence interval 23–28%) of patients had sub-optimal treatment response. Duration of therapy (P < 0.001), age at the start of therapy (P = 0.03), and baseline EDSS score (P < 0.001), were significantly different among treatments. Sub-optimal treatment response appeared to be related only to a more severe EDSS score at baseline and did not differ among therapies. Conclusion Neurologists should closely monitor patients to optimize treatment strategies and better control disease, improving prognosis. Electronic supplementary material The online version of this article (doi:10.1007/s40120-014-0019-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Maria José Sá
- Centro Hospitalar São João, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal
- Faculdade de Ciências da Saúde, Universidade Fernando Pessoa, Porto, Portugal
| | - João de Sá
- Centro Hospitalar Lisboa Norte, Hospital Santa Maria, Lisbon, Portugal
| | - Lívia Sousa
- Centro Hospitalar e Universitário de Coimbra, Hospitais da Universidade de Coimbra, Coimbra, Portugal
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A 2-year observational study of patients with relapsing-remitting multiple sclerosis converting to glatiramer acetate from other disease-modifying therapies: the COPTIMIZE trial. J Neurol 2014; 261:2101-11. [PMID: 25119836 PMCID: PMC4221652 DOI: 10.1007/s00415-014-7446-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Revised: 07/14/2014] [Accepted: 07/15/2014] [Indexed: 12/17/2022]
Abstract
Studies suggest that patients with relapsing-remitting multiple sclerosis (RRMS) who do not benefit from other disease-modifying treatments (DMTs) may benefit from converting to glatiramer acetate (GA). COPTIMIZE was a 24-month observational study designed to assess the disease course of patients converting to GA 20 mg daily from another DMT. Eligible patients had converted to GA and had received prior DMT for 3-6 months, depending on the reasons for conversion. Patients were assessed at baseline and at 6, 12, 18, and 24 months. In total, 672 patients from 148 centers worldwide were included in the analysis. Change of therapy to GA was prompted primarily by lack of efficacy (53.6 %) or intolerable adverse events (AEs; 44.8 %). Over a 24-month period, 72.7 % of patients were relapse free. Mean annual relapse rate decreased from 0.86 [95 % confidence interval (CI) 0.81-0.91] before the change to 0.32 (95 % CI 0.26-0.40; p < 0.0001) at last observation, while the progression of disability was halted, as the Kurtzke Expanded Disability Status Scale (EDSS) scores remained stable. Patients improved significantly (p < 0.05) on measures of fatigue, quality of life, depression, and cognition; mobility scores remained stable. The results indicate that changing RRMS patients to GA is associated with positive treatment outcomes.
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Broadley SA, Barnett MH, Boggild M, Brew BJ, Butzkueven H, Heard R, Hodgkinson S, Kermode AG, Lechner-Scott J, Macdonell RAL, Marriott M, Mason DF, Parratt J, Reddel SW, Shaw CP, Slee M, Spies J, Taylor BV, Carroll WM, Kilpatrick TJ, King J, McCombe PA, Pollard JD, Willoughby E. Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: an Australian and New Zealand perspective: part 3 treatment practicalities and recommendations. MS Neurology Group of the Australian and New Zealand Association of Neurologists. J Clin Neurosci 2014; 21:1857-65. [PMID: 24993136 DOI: 10.1016/j.jocn.2014.01.017] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Accepted: 01/28/2014] [Indexed: 11/29/2022]
Abstract
In this third and final part of our review of multiple sclerosis (MS) treatment we look at the practical day-to-day management issues that are likely to influence individual treatment decisions. Whilst efficacy is clearly of considerable importance, tolerability and the potential for adverse effects often play a significant role in informing individual patient decisions. Here we review the issues surrounding switching between therapies, and the evidence to assist guiding the choice of therapy to change to and when to change. We review the current level of evidence with regards to the management of women in their child-bearing years with regards to recommendations about treatment during pregnancy and whilst breast feeding. We provide a summary of recommended pre- and post-treatment monitoring for the available therapies and review the evidence with regards to the value of testing for antibodies which are known to be neutralising for some therapies. We review the occurrence of adverse events, both the more common and troublesome effects and those that are less common but have potentially much more serious outcomes. Ways of mitigating these risks and managing the more troublesome adverse effects are also reviewed. Finally, we make specific recommendations with regards to the treatment of MS. It is an exciting time in the world of MS neurology and the prospects for further advances in coming years are high.
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Affiliation(s)
- Simon A Broadley
- School of Medicine, Griffith University, Gold Coast Campus, QLD 4222, Australia; Department of Neurology, Gold Coast University Hospital, Southport, QLD, Australia.
| | - Michael H Barnett
- Brain and Mind Research Institute, University of Sydney, Camperdown, NSW, Australia
| | - Mike Boggild
- Department of Neurology, The Townsville Hospital, Douglas, QLD, Australia
| | - Bruce J Brew
- Department of Neurology and St Vincent's Centre for Applied Medical Research, St Vincent's Hospital, University of New South Wales, Darlinghurst, NSW, Australia
| | - Helmut Butzkueven
- Melbourne Brain Centre, Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia; Department of Neurology, Eastern Health and Monash University, 2/5 Arnold Street, Box Hill VIC 3128, Australia
| | - Robert Heard
- Westmead Clinical School, University of Sydney, NSW, Australia
| | - Suzanne Hodgkinson
- South Western Sydney Clinical School, University of New South Wales, NSW, Australia
| | - Allan G Kermode
- Centre for Neuromuscular and Neurological Disorders, University of Western Australia, WA, Australia
| | | | | | - Mark Marriott
- Melbourne Brain Centre, Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia
| | - Deborah F Mason
- Department of Neurology, Christchurch Hospital, Christchurch, New Zealand
| | - John Parratt
- Central Clinical School, University of Sydney, NSW, Australia
| | - Stephen W Reddel
- Brain and Mind Research Institute, University of Sydney, Camperdown, NSW, Australia
| | | | - Mark Slee
- Flinders Medical Centre, Flinders University, SA, Australia
| | - Judith Spies
- Brain and Mind Research Institute, University of Sydney, Camperdown, NSW, Australia
| | - Bruce V Taylor
- Menzies Research Institute, University of Tasmania, TAS, Australia
| | - William M Carroll
- Centre for Neuromuscular and Neurological Disorders, University of Western Australia, WA, Australia
| | | | - John King
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia
| | - Pamela A McCombe
- University of Queensland Centre for Clinical Research, QLD, Australia
| | - John D Pollard
- Brain and Mind Research Institute, University of Sydney, Camperdown, NSW, Australia
| | - Ernest Willoughby
- Department of Neurology, Auckland City Hospital, Auckland, New Zealand
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Carruthers RL, Rotstein DL, Healy BC, Chitnis T, Weiner HL, Buckle GJ. An observational comparison of natalizumab vs. fingolimod using JCV serology to determine therapy. Mult Scler 2014; 20:1381-90. [DOI: 10.1177/1352458514535282] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background: The lack of prospective trial data comparing certain multiple sclerosis (MS) therapies could be addressed with observational research. Objective: The objective of this paper is to investigate outcomes of natalizumab versus fingolimod treatment in an MS cohort using a novel method of patient selection. Methods: We reviewed entries from our clinic’s database for all relapsing–remitting MS patients started on fingolimod and natalizumab where JCV serology was used to determine treatment. We analyzed each group for time to first relapse and in a second analysis, time to first relapse or gadolinium-enhancing lesion. Results: Sixty-nine patients on natalizumab and 36 on fingolimod met our inclusion criteria and had adequate follow-up for analysis. The baseline clinical characteristics at the time of treatment switch were similar. With a mean follow-up of 1.5 years for both treatment groups, there was a trend favoring natalizumab in time to first relapse, although this was not statistically significant (2.20 (0.87, 5.55) p = 0.095). There was a significant difference in the secondary outcome, time to relapse or gadolinium-enhancing lesion (2.31 (1.03, 5.17) p = 0.041), favoring natalizumab. Adjusted analyses favored natalizumab for both outcomes ( p < 0.05). Conclusion: This work employed an observational study design where treatment allocation by JCV serology allowed for treatment groups with well-balanced characteristics.
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Affiliation(s)
- Robert L Carruthers
- Harvard Medical School, USA/Partners Multiple Sclerosis Center, Brigham and Women’s Hospital, USA
| | - Dalia L Rotstein
- Harvard Medical School, USA/Partners Multiple Sclerosis Center, Brigham and Women’s Hospital, USA
| | - Brian C Healy
- Harvard Medical School, USA/Partners Multiple Sclerosis Center, Brigham and Women’s Hospital, USA/Biostatistics Center, Massachusetts General Hospital, USA
| | - Tanuja Chitnis
- Harvard Medical School, USA/Partners Multiple Sclerosis Center, Brigham and Women’s Hospital, USA
| | - Howard L Weiner
- Harvard Medical School, USA/Partners Multiple Sclerosis Center, Brigham and Women’s Hospital, USA
| | - Guy J Buckle
- Harvard Medical School, USA/Partners Multiple Sclerosis Center, Brigham and Women’s Hospital, USA
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Khatri B, Pelletier J, Kappos L, Hartung HP, Comi G, Barkhof F, von Rosenstiel P, Meng X, Grinspan A, Hashmonay R, Cohen J. Effect of prior treatment status and reasons for discontinuation on the efficacy and safety of fingolimod vs. interferon β-1a intramuscular: Subgroup analyses of the Trial Assessing Injectable Interferon vs. Fingolimod Oral in Relapsing–Remitting Multiple Sclerosis (TRANSFORMS). Mult Scler Relat Disord 2014; 3:355-63. [DOI: 10.1016/j.msard.2013.11.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Revised: 11/13/2013] [Accepted: 11/20/2013] [Indexed: 10/25/2022]
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Teter B, Agashivala N, Kavak K, Chouhfeh L, Hashmonay R, Weinstock-Guttman B. Characteristics influencing therapy switch behavior after suboptimal response to first-line treatment in patients with multiple sclerosis. Mult Scler 2013; 20:830-6. [PMID: 24277325 DOI: 10.1177/1352458513513058] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2013] [Accepted: 10/22/2013] [Indexed: 11/17/2022]
Abstract
BACKGROUND Factors driving disease-modifying therapy (DMT) switch behavior are not well understood. OBJECTIVE The objective of this paper is to identify patient characteristics and clinical events predictive of therapy switching in patients with suboptimal response to DMT. METHODS This retrospective study analyzed patients with relapsing-remitting multiple sclerosis (MS) and a suboptimal response to initial therapy with either interferon β or glatiramer acetate. Suboptimal responders were defined as patients with ≥1 MS event (clinical relapse, worsening disability, or MRI worsening) while on DMT. Switchers were defined as those who changed DMT within six to 12 months after the MS event. RESULTS Of 606 suboptimal responders, 214 (35.3%) switched therapy. Switchers were younger at symptom onset (p = 0.012), MS diagnosis (p = 0.004), DMT initiation (p < 0.001), and first MS event (p = 0.011) compared with nonswitchers. Compared with one relapse alone, MRI worsening alone most strongly predicted switch behavior (odds ratio 6.3; 95% CI, 3.1-12.9; p < 0.001), followed by ≥2 relapses (2.8; 95% CI, 1.1-7.3; p = 0.040), EDSS plus MRI worsening (2.5; 95% CI, 1.1-5.9; p = 0.031) and EDSS worsening alone (2.2; 95% CI, 1.2-4.1; p = 0.009). CONCLUSIONS Younger patients with disease activity, especially MRI changes, are more likely to have their therapy switched sooner than patients who are older at the time of MS diagnosis and DMT initiation.
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Affiliation(s)
- Barbara Teter
- Department of Neurology, Jacobs Neurological Institute, State University of New York at Buffalo, USA New York State Multiple Sclerosis Consortium, USA
| | | | - Katelyn Kavak
- Department of Neurology, Jacobs Neurological Institute, State University of New York at Buffalo, USA New York State Multiple Sclerosis Consortium, USA
| | - Lynn Chouhfeh
- Department of Neurology, Jacobs Neurological Institute, State University of New York at Buffalo, USA
| | | | - Bianca Weinstock-Guttman
- Department of Neurology, Jacobs Neurological Institute, State University of New York at Buffalo, USA New York State Multiple Sclerosis Consortium, USA
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