{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T01:02:10Z","timestamp":1767142930343,"version":"build-2238731810"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"11","license":[{"start":{"date-parts":[[2018,8,1]],"date-time":"2018-08-01T00:00:00Z","timestamp":1533081600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2018,8,1]],"date-time":"2018-08-01T00:00:00Z","timestamp":1533081600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["CNS Drugs"],"published-print":{"date-parts":[[2018,11]]},"DOI":"10.1007\/s40263-018-0547-z","type":"journal-article","created":{"date-parts":[[2018,8,1]],"date-time":"2018-08-01T07:41:05Z","timestamp":1533109265000},"page":"1069-1078","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Oral Disease-Modifying Treatments for Relapsing Multiple Sclerosis: A Likelihood to Achieve No Evidence of Disease Activity or Harm Analysis"],"prefix":"10.1007","volume":"32","author":[{"given":"Dimitrios","family":"Papadopoulos","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4691-3388","authenticated-orcid":false,"given":"Dimos-Dimitrios D.","family":"Mitsikostas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2018,8,1]]},"reference":[{"key":"547_CR1","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1111\/ijcp.12142","volume":"67","author":"L Citrome","year":"2013","unstructured":"Citrome L, Ketter TA. When does a difference make a difference? Interpretation of number needed to treat, number needed to harm, and likelihood to be helped to harmed. Int J Clin Pract. 2013;67:407\u201311.","journal-title":"Int J Clin Pract"},{"key":"547_CR2","doi-asserted-by":"publisher","first-page":"e73","DOI":"10.4088\/JCP.16f11380","volume":"78","author":"C Andrade","year":"2017","unstructured":"Andrade C. Likelihood of being helped or harmed as a measure of clinical outcomes in psychopharmacology. J Clin Psychiatr. 2017;78:e73\u20135.","journal-title":"J Clin Psychiatr"},{"key":"547_CR3","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.jns.2017.10.015","volume":"383","author":"NE Parks","year":"2017","unstructured":"Parks NE, Flanagan EP, Lucchinetti CF, Wingerchuk DM. NEDA treatment target? No evident disease activity as an actionable outcome in practice. J Neurol Sci. 2017;383:31\u20134.","journal-title":"J Neurol Sci"},{"key":"547_CR4","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1016\/j.msard.2015.04.006","volume":"4","author":"G Giovannoni","year":"2015","unstructured":"Giovannoni G, Turner B, Gnanapavan S, Offiah C, Schmierer K, Marta M. Is it time to target no evident disease activity (NEDA) in multiple sclerosis? Mult Scler Relat Disord. 2015;4:329\u201333.","journal-title":"Mult Scler Relat Disord"},{"key":"547_CR5","doi-asserted-by":"publisher","first-page":"1179","DOI":"10.1177\/1352458517703193","volume":"23","author":"G Giovannoni","year":"2017","unstructured":"Giovannoni G, Tomic D, Bright JR, Havrdov\u00e1 E. \u201cNo evident disease activity\u201d: the use of combined assessments in the management of patients with multiple sclerosis. Mult Scler. 2017;23:1179\u201387.","journal-title":"Mult Scler."},{"key":"547_CR6","first-page":"822","volume":"23","author":"AL Hincapie","year":"2017","unstructured":"Hincapie AL, Penm J, Burns CF. Factors associated with patient preferences for disease-modifying therapies in multiple sclerosis. J Manag Care Spec Pharm. 2017;23:822\u201330.","journal-title":"J Manag Care Spec Pharm."},{"key":"547_CR7","first-page":"1394","volume":"22","author":"L Higuera","year":"2016","unstructured":"Higuera L, Carlin CS, Anderson S. adherence to disease-modifying therapies for multiple sclerosis. J Manag Care Spec Pharm. 2016;22:1394\u2013401.","journal-title":"J Manag Care Spec Pharm."},{"key":"547_CR8","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.msard.2017.08.003","volume":"18","author":"DD Mitsikostas","year":"2017","unstructured":"Mitsikostas DD, Goodin DS. Comparing the efficacy of disease modifying therapies in multiple sclerosis. Mult Scler Relat Disord. 2017;18:109\u201316.","journal-title":"Mult Scler Relat Disord"},{"key":"547_CR9","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1007\/s40263-016-0377-9","volume":"30","author":"D Mendes","year":"2016","unstructured":"Mendes D, Alves C, Batel-Marques F. Benefit-risk of therapies for relapsing-remitting multiple sclerosis: testing the number needed to treat to benefit (NNTB), number needed to treat to harm (NNTH) and the likelihood to be helped or harmed (LHH): a systematic review and meta-analysis. CNS Drugs. 2016;30:909\u201329.","journal-title":"CNS Drugs"},{"key":"547_CR10","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1016\/j.msard.2016.10.010","volume":"10","author":"MS Freedman","year":"2016","unstructured":"Freedman MS, Montalban X, Miller AE, Dive-Pouletty C, Hass S, Thangavelu K, et al. Comparing outcomes from clinical studies of oral disease-modifying therapies (dimethyl fumarate, fingolimod, and teriflunomide) in relapsing MS: assessing absolute differences using a number needed to treat analysis. Mult Scler Relat Disord. 2016;10:204\u201312.","journal-title":"Mult Scler Relat Disord."},{"key":"547_CR11","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1056\/NEJMoa0902533","volume":"362","author":"G Giovannoni","year":"2010","unstructured":"Giovannoni G, Comi G, Cook S, Rammohan K, Rieckmann P, Soelberg Sorensen P, et al. CLARITY study Group. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010;362:416\u201326.","journal-title":"N Engl J Med"},{"key":"547_CR12","doi-asserted-by":"publisher","first-page":"1098","DOI":"10.1056\/NEJMoa1114287","volume":"367","author":"R Gold","year":"2012","unstructured":"Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, et al. DEFINE\u00a0Study Investigators. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367:1098\u2013107.","journal-title":"N Engl J Med"},{"key":"547_CR13","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.1056\/NEJMoa1206328","volume":"367","author":"RJ Fox","year":"2012","unstructured":"Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, et al. CONFIRM\u00a0Study Investigators. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in\u00a0multiple sclerosis. N Engl J Med. 2012;367:1087\u201397.","journal-title":"N Engl J Med"},{"key":"547_CR14","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1056\/NEJMoa0909494","volume":"362","author":"L Kappos","year":"2010","unstructured":"Kappos L, Radue E-W, O\u2019Connor P, Polman C, Hohlfeld R, Calabresi P, et al. FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362:387\u2013401.","journal-title":"N Engl J Med"},{"key":"547_CR15","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1016\/S1474-4422(14)70049-3","volume":"13","author":"PA Calabresi","year":"2014","unstructured":"Calabresi PA, Radue E-W, Goodin D, Jeffery D, Rammohan KW, Reder AT, et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomized, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13:545\u201356.","journal-title":"Lancet Neurol"},{"key":"547_CR16","doi-asserted-by":"publisher","first-page":"1293","DOI":"10.1056\/NEJMoa1014656","volume":"365","author":"P O\u2019Connor","year":"2011","unstructured":"O\u2019Connor P, Wolinsky JS, Confavreux C, Comi G, Kappos L, Olsson TP, et al. TEMSO Trial Group. Randomised trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365:1293\u2013303.","journal-title":"N Engl J Med"},{"key":"547_CR17","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/S1474-4422(13)70308-9","volume":"13","author":"C Confavreaux","year":"2014","unstructured":"Confavreaux C, O\u2019Connor P, Comi G, Freedman MS, Miller AE, Olsson TP, et al. TOWER Trial Group. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13:247\u201356.","journal-title":"Lancet Neurol"},{"key":"547_CR18","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1111\/ene.13272","volume":"24","author":"E Havrdova","year":"2017","unstructured":"Havrdova E, Giovannoni G, Gold R, Fox RJ, Kappos L, Phillips JT, et al. Effect of delayed-release dimethyl fumarate on no evidence of disease activity in relapsing-remitting multiple sclerosis: integrated analysis of the phase III DEFINE and CONFIRM studies. Eur J Neurol. 2017;24:726\u201333.","journal-title":"Eur J Neurol"},{"key":"547_CR19","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1002\/acn3.148","volume":"2","author":"V Viglietta","year":"2015","unstructured":"Viglietta V, Miller D, Bar-Or A, Phillips JT, Arnold DL, Selmaj K, et al. Efficacy of delayed-release dimethyl fumarate in relapsing-remitting multiple sclerosis: integrated analysis of the phase III trials. Ann Clin Transl Neurol. 2015;2:103\u201318.","journal-title":"Ann Clin Transl Neurol."},{"key":"547_CR20","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.1177\/1352458515616701","volume":"22","author":"L Kappos","year":"2016","unstructured":"Kappos L, De Stefano N, Freedman MS, Cree BA, Radue EW, Sprenger T, et al. Inclusion of brain volume loss in a revised measure of \u2018no evidence of disease activity\u2019 (NEDA-4) in relapsing-remitting multiple sclerosis. Mult Scler J. 2016;22:1297\u2013305.","journal-title":"Mult Scler J"},{"key":"547_CR21","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1016\/S1474-4422(11)70023-0","volume":"10","author":"G Giovannoni","year":"2011","unstructured":"Giovannoni G, Cook S, Rammohan K, Rieckmann P, S\u00f8rensen PS, Vermersch P, et al. CLARITY study group. Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post hoc and subgroup analysis. Lancet Neurol. 2011;10:329\u201337.","journal-title":"Lancet Neurol."},{"issue":"suppl","key":"547_CR22","first-page":"PD5.007","volume":"78","author":"M Freedman","year":"2012","unstructured":"Freedman M, O\u2019Connor P, Wolinsky J, Confavreux C, Comi G, Kappos L, et al. Teriflunomide increases the proportion of patients free from disease activity in the TEMSO phase III study. Neurology. 2012;78(suppl):PD5.007.","journal-title":"Neurology"},{"key":"547_CR23","doi-asserted-by":"publisher","first-page":"1309","DOI":"10.1136\/bmj.317.7168.1309","volume":"317","author":"DG Altman","year":"1998","unstructured":"Altman DG. Confidence intervals for the number needed to treat. BMJ. 1998;317:1309\u201312.","journal-title":"BMJ"},{"key":"547_CR24","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1177\/1352458514558678","volume":"21","author":"D Dahdaleh","year":"2015","unstructured":"Dahdaleh D, Sharrack B. We can compare the relative efficacy of multiple sclerosis medications by examining the results of independent clinical trials: yes. Mult Scler J. 2015;21:35\u20136.","journal-title":"Mult Scler J"},{"key":"547_CR25","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1177\/1352458514559866","volume":"21","author":"O Ciccarelli","year":"2015","unstructured":"Ciccarelli O, Chataway J. We can compare the relative efficacy of multiple sclerosis medications by examining the results of independent clinical trials: no. Mult Scler J. 2015;21:37\u20138.","journal-title":"Mult Scler J"},{"key":"547_CR26","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/j.msard.2015.03.009","volume":"4","author":"M Zakaria","year":"2015","unstructured":"Zakaria M. Smoke and mirrors: limited value of relative risk reductions for assessing the benefits of disease-modifying therapies for multiple sclerosis. Mult Scler Relat Disord. 2015;4:187\u201391.","journal-title":"Mult Scler Relat Disord"},{"key":"547_CR27","doi-asserted-by":"crossref","unstructured":"Goodin DS. Disease-modifying therapy in multiple sclerosis: update and clinical implications. Neurology 2008;71:(24 Suppl 3) S8\u201313.","DOI":"10.1212\/WNL.0b013e31818f3d8b"},{"key":"547_CR28","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1111\/j.1600-0447.2009.01449.x","volume":"121","author":"L Citrome","year":"2010","unstructured":"Citrome L. Relative vs. absolute measures of benefit and risk: what\u2019s the difference? Acta Psychiatr Scand. 2010;121:94\u2013102.","journal-title":"Acta Psychiatr Scand"},{"key":"547_CR29","doi-asserted-by":"publisher","first-page":"1134","DOI":"10.1007\/s12325-014-0167-z","volume":"31","author":"R Nixon","year":"2014","unstructured":"Nixon R, Bergvall N, Tomic D, Sfikas N, Cutter G, Giovannoni G. No evidence of disease activity: indirect comparisons of oral therapies for the treatment of relapsing-remitting multiple sclerosis. Adv Ther. 2014;31:1134\u201356.","journal-title":"Adv Ther"},{"key":"547_CR30","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/j.msard.2018.03.011","volume":"21","author":"DS Goodin","year":"2018","unstructured":"Goodin DS, Mitsikostas DD. Reply to Tsivgoulis and colleagues comments [letter]. Mult Scler Relat Disord. 2018;21:120\u20131.","journal-title":"Mult Scler Relat Disord"},{"key":"547_CR31","first-page":"1","volume":"15","author":"HH Goltz","year":"2010","unstructured":"Goltz HH, Smith ML. Yule-Simpson\u2019s paradox in research. Pract Assess Res Eval. 2010;15:1\u20139.","journal-title":"Pract Assess Res Eval"}],"updated-by":[{"DOI":"10.1007\/s40263-018-0595-4","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2018,12,20]],"date-time":"2018-12-20T00:00:00Z","timestamp":1545264000000}}],"container-title":["CNS Drugs"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s40263-018-0547-z\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s40263-018-0547-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s40263-018-0547-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,11,2]],"date-time":"2020-11-02T13:14:24Z","timestamp":1604322864000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s40263-018-0547-z"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,8,1]]},"references-count":31,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2018,11]]}},"alternative-id":["547"],"URL":"https:\/\/doi.org\/10.1007\/s40263-018-0547-z","relation":{},"ISSN":["1172-7047","1179-1934"],"issn-type":[{"value":"1172-7047","type":"print"},{"value":"1179-1934","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,8,1]]},"assertion":[{"value":"1 August 2018","order":1,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 December 2018","order":2,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":3,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"NEDA was evaluated as the proportion of patients free of relapses, 3-month confirmed disability progression, and free of new or newly enlarging T2 lesion and Gadolinium enhancing lesions.","order":4,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with Ethical Standards"}},{"value":"No ethics approval or patient consent was obtained because all data used in this study were collected from previously published peer-reviewed articles.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical Approval and Consent"}},{"value":"DP has received consulting, speaking fees, and travel grants from Bayer, Genesis Pharma, Merck, Novartis, Roche, Sanofi-Aventis, Specifar, and Teva. DDM has received consulting, speaking fees, and travel grants from Allergan, Amgen, Cefaly, ElectroCore, Genesis Pharma, Eli Lily, Merck-Serono, Novartis, Roche, Sanofi-Genzyme, Speficar, and Teva.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"No funding source had a role in the conception and preparation of this article.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}}]}}