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April 24, 2018; 90 (17) Special Article

Comprehensive systematic review summary: Disease-modifying therapies for adults with multiple sclerosis

Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology

Alexander Rae-Grant, Gregory S. Day, Ruth Ann Marrie, Alejandro Rabinstein, Bruce A.C. Cree, Gary S. Gronseth, Michael Haboubi, June Halper, Jonathan P. Hosey, David E. Jones, Robert Lisak, Daniel Pelletier, Sonja Potrebic, Cynthia Sitcov, Rick Sommers, Julie Stachowiak, Thomas S.D. Getchius, Shannon A. Merillat, Tamara Pringsheim
First published April 23, 2018, DOI: https://doi.org/10.1212/WNL.0000000000005345
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Abstract

Objective To review evidence on starting, switching, and stopping disease-modifying therapies (DMTs) for multiple sclerosis (MS) in clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and progressive MS forms.

Methods Relevant, peer-reviewed research articles, systematic reviews, and abstracts were identified (MEDLINE, CENTRAL, EMBASE searched from inception to November 2016). Studies were rated using the therapeutic classification scheme. Prior published Cochrane reviews were also used.

Results Twenty Cochrane reviews and an additional 73 full-text articles were selected for data extraction through an updated systematic review (completed November 2016). For people with RRMS, many DMTs are superior to placebo (annualized relapses rates [ARRs], new disease activity [new MRI T2 lesion burden], and in-study disease progression) (see summary and full text publications). For people with RRMS who experienced a relapse on interferon-β (IFN-β) or glatiramer acetate, alemtuzumab is more effective than IFN-β-1a 44 μg subcutaneous 3 times per week in reducing the ARR. For people with primary progressive MS, ocrelizumab is probably more effective than placebo (in-study disease progression). DMTs for MS have varying adverse effects. In people with CIS, glatiramer acetate and IFN-β-1a subcutaneous 3 times per week are more effective than placebo in decreasing risk of conversion to MS. Cladribine, immunoglobulins, IFN-β-1a 30 μg intramuscular weekly, IFN-β-1b subcutaneous alternate day, and teriflunomide are probably more effective than placebo in decreasing risk of conversion to MS. Suggestions for future research include studies considering comparative effectiveness, usefulness of high-efficacy treatment vs stepped-care protocols, and research into predictive biomarkers.

Glossary

AAN=
American Academy of Neurology;
AE=
adverse effect;
ARR=
annualized relapse rate;
CIS=
clinically isolated syndromes;
DMT=
disease-modifying therapy;
EDSS=
Expanded Disability Status Scale;
HYP=
high-yield process;
IFN-β=
interferon-β;
IM=
intramuscular;
MS=
multiple sclerosis;
PPMS=
primary progressive multiple sclerosis;
RCT=
randomized controlled trial;
RRMS=
relapsing-remitting multiple sclerosis;
SPMS=
secondary progressive multiple sclerosis

This article summarizes the findings and conclusions of an American Academy of Neurology (AAN) practice guideline on the efficacy and safety of disease-modifying therapies (DMTs) in multiple sclerosis (MS). References e1 through e49, cited here, are available at links.lww.com/WNL/A374 as a data supplement to this summary article.

A companion article presents the recommendations and suggestions for future research.1 The complete practice guideline (systematic review, recommendations, and suggestions for future research) is available at links.lww.com/WNL/A429 as a data supplement to the companion recommendations article. This guideline, although not a formal update to the 2002 AAN guideline on DMTs,2 replaces that earlier guideline. The complete guideline includes full details of the methodology used, including risk of bias classification for each study, confidence in the evidence determinations, and rationales for recommendation strength; space restrictions precluded more detailed description in this article.

MS affects more than 400,000 people in the United States and more than 2.3 million people worldwide.3 Since 1993, DMTs have been approved in the United States for treating relapsing forms of MS; most of these therapies are approved for use in other countries. Many additional medications have been used off-label for MS disease modification.

Multiple new DMTs have become available since publication of the 2002 AAN practice guideline on DMTs in MS.2 Clinicians and people with MS may now choose from several medications, with differing mechanisms of action, risk profiles, and monitoring requirements. Before recommending a specific therapy, the clinician must navigate these complexities while carefully balancing the potential for therapeutic benefits of a medication with patient preferences, monitoring recommendations, drug- and individual-specific risk factors, and concerns regarding the long-term risk of MS-related disability and morbidity.

The new practice guideline,1 based on the systematic review summarized here, provides guidance concerning current issues surrounding DMT for MS prescribing, specifically addressing the following questions pertinent to clinically isolated syndromes of demyelination (CIS), relapsing-remitting MS (RRMS), and progressive forms of MS (secondary progressive MS [SPMS] and primary progressive MS [PPMS]):

  1. In people with RRMS, are DMTs superior to placebo or other DMTs as measured by annualized relapse rates (ARRs) and the relative risk of relapse at 2 years?

  2. In people with RRMS, are DMTs superior to placebo or other DMTs in reducing MRI-detected new disease activity as measured by new T2 lesion burden or atrophy measures?

  3. In people with RRMS, are DMTs superior to placebo or other DMTs in preventing disease progression as measured by in-study disease progression measures?

  4. In people with RRMS who experience disease activity while on a DMT, is changing to a different DMT superior to continuing the present DMT in terms of relapse rate and MRI-detected T2 or gadolinium-enhanced lesion activity?

  5. In people with progressive MS, are DMTs superior to placebo or other DMTs as measured by relapse rate or in-study disease progression?

  6. What are the adverse effects (AEs) of DMTs in people with MS compared with placebo (AE-related discontinuation and serious or life-threatening AEs)?

  7. In people with CIS, are DMTs superior to placebo in decreasing the risk of conversion to MS?

Description of the analytic process

In May 2015, the AAN guideline subcommittee recruited a multidisciplinary panel to develop the guideline on which this systematic review is based. The panel consists of 12 AAN physician and nurse members, 2 representatives from the Consortium of Multiple Sclerosis Centers, and 3 patient representatives. Two AAN staff representatives were also appointed to the panel. Conflicts of interest were reviewed by the panel leadership; panelists with conflicts did not participate in systematic review development.

The practice guideline follows the methodologies described in the 2011 edition of the AAN's guideline development process manual, as amended to include an updated classification scheme for therapeutic studies, a formalized prioritization process for guideline topic nominations, and a change in the order of steps for the external (peer) review process.4 Institute of Medicine standards for systematic review and clinical practice guideline development were adhered to throughout the development process, including posting of the protocol and draft document with recommendations for public review and active solicitation of patient input.5,6 For the systematic review, the panel used appropriate Cochrane reviews (assessed by 2 panelists working independently of each other and using A Measurement Tool to Assess Systematic Reviews quality)7 in addition to treatment-specific systematic reviews. Two nonconflicted panelists working independently reviewed abstracts for article inclusion. From their review, full-text articles were obtained for data extraction, and risk of bias was established by 2 panelists rating articles independently of each other. Data extraction was performed by the AAN staff guideline methodologist and confirmed by panel members. The panel considered data for efficacy outcomes from randomized controlled trials (RCTs). For harms, the panel considered data from RCTs, cohort studies, case reports, and case series. Meta-analyses were performed when appropriate. Before data analysis, the panel completed an anonymous survey to establish the minimal clinically meaningful difference for measures of DMT efficacy and AEs; this information was used in the analytic portion of the guideline. Conclusions were developed using a modified Grading of Recommendations, Assessment, Development and Evaluation process.8

Analysis of evidence

Twenty Cochrane systematic reviews were identified and used in the evidence review process. These systematic reviews included data from 70 RCTs, which were included in the panel's evidence synthesis. For the update of the Cochrane reviews and de novo systematic review (completed November 2016), the combined searches yielded 4,301 abstracts. Each abstract was reviewed for relevance by at least 2 panel members, who deemed 284 as relevant. The corresponding articles were obtained for full-text review by 2 panelists working independently of each other. An additional 73 articles were identified for data extraction.

All trials included individuals with MS aged 18 years or older. The maximum age of participants varied across trials but was usually between 50 and 60 years. Most studies were 2 years in length (range 6 months–3 years). Trials occurred in multiple countries worldwide. Twenty-three DMTs were systematically reviewed: methotrexate, cyclophosphamide, pulsed corticosteroids for disease modification, interferon-β (IFN-β) (4 types: IFN-β-1b subcutaneous alternate day, IFN-β-1a intramuscular [IM] subcutaneous, pegylated IFN subcutaneous every other week, IFN-β-1a subcutaneous 3 times per week), glatiramer acetate (3 types: proprietary daily 20-mg subcutaneous form, proprietary 3-day-per-week 40-mg subcutaneous form, generic 20-mg subcutaneous daily form), natalizumab, azathioprine, teriflunomide, mycophenolate mofetil, rituximab, ocrelizumab, daclizumab, mitoxantrone, alemtuzumab, fingolimod, dimethyl fumarate, IV immunoglobulin for disease modification, and cladribine.

Safety note: After US Food and Drug Administration (FDA) approval was received, daclizumab (ZINBRYTA) was voluntarily removed from the market on March 2, 2018, by its manufacturers, Biogen and AbbVie, due to serious adverse events in relapsing MS.8a

The results of the systematic review support the following evidence-based conclusions. All recommendations are provided in the companion publication.1

1. In people with RRMS, are DMTs superior to placebo or other DMTs as measured by ARRs and the relative risk of relapse at 2 years?

For this question, figure 1 presents the data regarding ARRs, and figure 2 presents the data on the relative risk of relapse at 2 years. The table shows the findings and conclusions for both the ARRs and the relative risk of relapse at 2 years.

Figure 1
Figure 1 Outcome: Annualized relapse rate, relapsing-remitting multiple sclerosis

IVIg = IV immunoglobulin; LCL = lower confidence limit; RM = raw mean difference; UCL = upper confidence limit. aVersus interferon-β-1a 44 μg 3 times per week subcutaneously. bSee safety note on page 791.8a

Figure 2
Figure 2 Outcome: Relative risk of relapse at 2 years, relapsing-remitting multiple sclerosis

IVIg = IV immunoglobulin; LCL = lower confidence limit; RR = risk ratio; UCL = upper confidence limit. aRelative to interferon alone. bOutcome assessed at 18 months. cOutcome assessed at 1 year. dSee safety note on page 791.8a

View this table:
Table

Efficacy of disease-modifying therapies (DMTs) for reducing the annualized relapse rate (ARR) and risk of relapse at 2 years

2. In people with RRMS, are DMTs superior to placebo or other DMTs in reducing MRI new disease activity as measured by new T2 lesion burden or atrophy measures?

Risk of new or enlarging T2 lesions

The following DMTs are more effective than placebo in reducing the risk of MRI-detected new or enlarging T2 lesions (high confidence): fingolimod,9,10 IFN-β-1a 44 μg subcutaneous 3 times weekly,11 and natalizumab.12

Ocrelizumab13 is more effective than IFN-β-1a subcutaneous 3 times per week in reducing the risk of new or enlarging T2 lesions detected by MRI (high confidence).

Cladribine14 is probably more effective than placebo in reducing the risk of new or enlarging T2 lesions detected by MRI (moderate confidence).

The following DMTs are probably more effective than other DMTs in reducing the risk of MRI-detected new or enlarging T2 lesions (moderate confidence): alemtuzumab (vs IFN-β-1a subcutaneous 3 times per week),15 fingolimod (vs IFN-β-1a IM once weekly),16 IFN-β-1a 44 μg subcutaneous 3 times weekly (vs IFN-β-1a IM once weekly).17

IFN-β-1a subcutaneous 3 times per week is possibly no more effective than glatiramer acetate in decreasing the risk of MRI-detected new or enlarging T2 lesions (low confidence).18

There is insufficient evidence to determine the efficacy of azathioprine compared with IFN-β19 in reducing the risk of MRI-detected new or enlarging T2 lesions (very low confidence).

Reducing the volume or number of T2 lesions

The following DMTs are more effective than placebo in reducing the volume or number of MRI-detected T2 lesions (high confidence): daclizumab high-yield process (HYP),20 dimethyl fumarate,18,21 glatiramer acetate,18 IFN-β-1a 30 μg IM weekly,22 mitoxantrone,23 natalizumab,12 and pegylated IFN.24 See the safety note on this page.8a

Rituximab25 and teriflunomide26 are probably more effective than placebo in reducing the volume or number of MRI-detected T2 lesions (moderate confidence).

The following DMTs are probably more effective than other DMTs in reducing the volume or number of MRI-detected T2 lesions (moderate confidence): alemtuzumab (vs IFN-β-1a subcutaneous 3 times per week)15 and daclizumab (vs IFN-β-1a IM once weekly).27 See safety note on page 791.8a

There is insufficient evidence to determine the efficacy of mycophenolate mofetil vs IFN-β-1a once weekly for reducing the volume or number of MRI-detected T2 lesions (very low confidence).28

There is insufficient evidence to determine the efficacy of pulsed corticosteroids29 relative to placebo for reducing the volume or number of MRI-detected T2 lesions (very low confidence).

Reducing loss of parenchymal volume

Ocrelizumab13 is more effective than IFN-β-1a 44 μg subcutaneous 3 times weekly in reducing loss of parenchymal volume (high confidence).

Alemtuzumab is probably more effective than IFN-β-1a 44 μg subcutaneous 3 times weekly29 in reducing loss of parenchymal volume (moderate confidence).

Pulsed corticosteroids30 are probably more effective than placebo in reducing loss of parenchymal volume (moderate confidence).

There is insufficient evidence to determine the efficacy of the following DMTs relative to placebo in reducing loss of parenchymal volume (very low confidence): IFN-β-1a 30 μg IM weekly22 and mycophenolate mofetil added to IFN-β-1a 30 μg IM weekly.31

3. In people with RRMS, are DMTs superior to placebo or other DMTs in preventing disease progression as measured by in-study disease progression measures?

The most consistently reported measure for in-study disability progression was the proportion of people with MS with disability progression. Disability progression was defined by an increase in the Expanded Disability Status Scale (EDSS) of 1 point in those with a baseline EDSS score of 5.0 or lower, or an increase of 0.5 point in those with a baseline EDSS score of 5.5 or higher, sustained for 3 or 6 months, and detected over a 2-year study period (figure 3).

Figure 3
Figure 3 Outcome: Relative risk (RR) of in-study disability progression at 2 years, relapsing-remitting multiple sclerosis

IVIg = IV immunoglobulin; LCL = lower confidence limit; UCL = upper confidence limit. aOutcome measured at 1 year. bVersus interferon-β-1a. cOutcome measured at 3 years. dSee safety note on page 791.8a

The following DMTs are more effective than placebo in reducing the risk of disability progression in people with RRMS (high confidence): daclizumab HYP,20 dimethyl fumarate,18,21 fingolimod,9,10 IFN-β-1a 30 μg IM weekly,22,32 IFN-β-1a 44 μg subcutaneous 3 times weekly,11 mitoxantrone,23 natalizumab,12 pegylated IFN,24 and teriflunomide.26,33 See safety note on page 791.8a

The following DMTs are more effective than other DMTs in reducing the risk of disability progression in people with RRMS (high confidence): alemtuzumab (vs IFN-β-1a 44 μg subcutaneous 3 times weekly) 15,29 and ocrelizumab (vs IFN-β-1a 44 μg subcutaneous 3 times weekly).13

Cladribine14 is probably more effective than placebo in reducing the risk of disability progression in people with RRMS (moderate confidence).

Daclizumab is probably more effective than IFN-β-1a 30 μg IM27 in reducing the risk of disability progression in people with RRMS (moderate confidence). See safety note on page 791.8a

Pulsed corticosteroids30 are possibly more effective than placebo in reducing the risk of disability progression in people with RRMS (low confidence).

The following DMTs are possibly no more effective than placebo in reducing the risk of disability progression in people with RRMS (low confidence): glatiramer acetate18,34,35 and pulsed corticosteroids added to IFN-β-1a IM once weekly.36

Fingolimod is possibly no more effective than IFN-β-1a IM weekly in reducing the risk of disability progression over 1 year (low confidence).16 See safety note on page 791.8a

IFN-β-1a is possibly no more effective than glatiramer acetate in reducing the risk of disability progression over 3 years (low confidence).37

There is insufficient evidence to determine the efficacy of the following DMTs compared with placebo in reducing the risk of disability progression in people with RRMS (very low confidence): azathioprine,38 immunoglobulins,39,40 IFN-β-1b subcutaneous alternate day,e1 and methotrexate.e2

IFN-β-1b alternate day is probably less effective than glatiramer acetate in reducing the risk of disability progression over 2 years (moderate confidence).e1

4. In people with RRMS who experience disease activity while on a DMT, is changing to a different DMT superior to continuing the present DMT in terms of relapse rate and MRI-detected T2 or gadolinium-enhanced lesion activity?

For individuals with RRMS who experienced a relapse on IFN-β or glatiramer acetate, alemtuzumab is more effective than IFN-β-1a 44 μg subcutaneous 3 times per week in reducing the ARR, the relapse risk, disability progression, and risk of new or enlarging T2 lesions over 2 years (high confidence).15

In individuals with RRMS who experience 1 or more relapses in the preceding 12 months on IFN-β, adding natalizumab is more effective than adding placebo in decreasing the risk of relapse over 2 years, the ARR, the risk of disability progression over 2 years, and the risk of new or enlarging T2 lesions at 1 year (high confidence).e3

In individuals with RRMS who experienced one or more relapses in the preceding 12 months on glatiramer acetate, there is insufficient evidence to determine the efficacy of natalizumab added to glatiramer acetate compared with placebo added to glatiramer acetate in decreasing the risk of relapse at 6 months (very low confidence).e4

Natalizumab added to glatiramer acetate is probably more effective than placebo added to glatiramer acetate in decreasing the cumulative number of new or enlarging T2 lesions at 6 months (moderate confidence).e4

Note that natalizumab is not presently approved/recommended as an add-on therapy to other DMTs owing to potential safety concerns associated with combined use of this medication.

5. In people with progressive MS, are DMTs superior to placebo or other DMTs as measured by relapse rate or in-study disease progression?

Risk of relapse

Figure 4 presents these data regarding risk of relapse. IFN-β-1b subcutaneous alternate day (SPMS) is more effective than placebo in reducing the risk of relapse in people with progressive MS (high confidence).e5,e6

Figure 4
Figure 4 Outcome: Relative risk (RR) of relapse at 2 years secondary progressive multiple sclerosis

IVIg = IV immunoglobulin; LCL = lower confidence limit; UCL = upper confidence limit. aHigh-dose corticosteroids vs low-dose corticosteroids. bOutcome measured at 3 years.

The following DMTs are probably more effective than placebo in reducing the risk of relapse in people with progressive MS (moderate confidence): IFN-β-1a 60 μg IM weekly (SPMS)e7 and mitoxantrone (worsening RRMS and SPMS).e8

There is insufficient evidence to determine the efficacy of the following DMTs compared with placebo in reducing the risk of relapse in people with progressive MS (very low confidence): azathioprine,38 immunoglobulins,e9,e10 and methotrexate (chronic progressive MS, older terminology that is undefined but included present PPMS and SPMS disease types).e11 There is insufficient evidence to determine the efficacy of high-dose corticosteroids compared with low-dose corticosteroidse12 in reducing the risk of relapse in people with SPMS (very low confidence).

Disability progression

The following DMTs are probably more effective than placebo in reducing the risk of in-study disability progression in people with progressive MS (RRMS or SPMS; moderate confidence): mitoxantrone (worsening RRMS and SPMS)e13 and ocrelizumab (PPMS).e14

The following DMTs are possibly no more effective than placebo in reducing the risk of in-study disability progression in people with progressive MS (low confidence): cladribine (SPMS),e15 fingolimod (PPMS),e16 glatiramer acetate (progressive forms of MSe17 and PPMSe18), IFN-β-1a 30 μg IM weekly (SPMSe7 and PPMSe19), IFN-β-1a subcutaneous 3 times per week (SPMS),e20 IFN-β-1b subcutaneous alternate day (SPMSe5,e6 and PPMSe21), and rituximab (PPMS).e22

There is insufficient evidence to determine the efficacy of the following DMTs relative to placebo in reducing the risk of in-study disability progression in people with progressive MS (very low confidence): azathioprine,38 corticosteroids added to mitoxantrone,e23 cyclophosphamide,e24,e25 immunoglobulins,e9,e10 and methotrexate (CPMS [PPMS]).e11

There is insufficient evidence to determine the efficacy of high-dose corticosteroids relative to low-dose corticosteroidse26 in reducing the risk of in-study disability progression in people with progressive MS (very low confidence).

6. What are the AEs of DMTs in people with MS compared with placebo (AE-related discontinuation and serious or life-threatening AEs)?

A comprehensive review of adverse effects associated with DMTs is included in the full-text document (data supplement to the companion recommendations article, links.lww.com/WNL/A429) and table.

7. In people with CIS, are DMTs superior to placebo in decreasing the risk of conversion to MS?

Figure 5 presents the data regarding risk of conversion to MS in people with CIS. For individuals with CIS, the following DMTs are more effective than placebo in reducing the proportion of individuals converting to MS (high confidence): glatiramer acetatee27 and IFN-β-1a subcutaneous 3 times weekly.e28

Figure 5
Figure 5 Outcome: Relative risk (RR) of conversion to multiple sclerosis over 2 years

IVIg = IV immunoglobulin; LCL = lower confidence limit; UCL = upper confidence limit. aOutcome measured at 1 year. bOutcome measured at 3 years.

For individuals with CIS, the following DMTs are probably more effective than placebo in reducing the proportion of individuals converting to MS (moderate confidence): cladribine,e29 immunoglobulins,e30 IFN-β-1a 30 μg IM weekly,e31 IFN-β-1b subcutaneous alternate day,e32 and teriflunomide.e33

Discussion

Multiple DMTs are now approved for use in CIS or MS, allowing people with MS and clinicians to consider DMT mechanism of action, efficacy, and AE profile in the decision-making process. This systematic review was used to develop a practice guideline for the use of DMT for MS, acknowledging the limits of current evidence. Measures of efficacy such as long-term disability, patient satisfaction, quality of life, and effects on MS symptoms may be important to the decision-making process but ultimately remain inadequately studied. Similarly, there is a dearth of high-quality evidence pertaining to the comparative efficacy of specific DMTs or various treatment strategies (e.g., high-efficacy treatment vs stepped-care treatment protocols). Future studies addressing these and other questions are needed to further inform treatment recommendations, particularly those pertaining to when to switch or stop DMTs.

Author contributions

Dr. Rae-Grant: study concept and design, acquisition of data, analysis or interpretation of data, drafting/revising the manuscript, critical revision of the manuscript for important intellectual content, study supervision. Dr. Day: study concept and design, analysis or interpretation of data, drafting/revising the manuscript, critical revision of the manuscript for important intellectual content. Dr. Marrie: study concept and design, acquisition of data, analysis or interpretation of data, drafting/revising the manuscript, critical revision of the manuscript for important intellectual content. Dr. Rabinstein: analysis or interpretation of data, drafting/revising the manuscript. Dr. Cree: study concept and design, drafting/revising the manuscript, critical revision of the manuscript for important intellectual content. Dr. Gronseth: analysis or interpretation of data, critical revision of the manuscript for important intellectual content, study supervision. Dr. Haboubi: study concept and design, analysis or interpretation of data, drafting/revising the manuscript. J. Halper: study concept and design, drafting/revising the manuscript, critical revision of the manuscript for important intellectual content. Dr. Hosey: critical revision of the manuscript for important intellectual content. Dr. Jones: study concept and design, drafting/revising the manuscript, critical revision of the manuscript for important intellectual content. Dr. Lisak: study concept and design, drafting/revising the manuscript, critical revision of the manuscript for important intellectual content. Dr. Pelletier: study concept and design, drafting/revising the manuscript, critical revision of the manuscript for important intellectual content. Dr. Potrebic: study concept and design, acquisition of data, analysis or interpretation of data, drafting/revising the manuscript, critical revision of the manuscript for important intellectual content, study supervision. C. Sitcov: study concept and design, drafting/revising the manuscript, critical revision of the manuscript for important intellectual content. R. Sommers: drafting/revising the manuscript, critical revision of the manuscript for important intellectual content. Dr. Stachowiak: study concept and design, drafting/revising the manuscript, critical revision of the manuscript for important intellectual content. T.S.D. Getchius: study supervision. S.A. Merillat: drafting/revising the manuscript, study supervision. Dr. Pringsheim: study concept and design, acquisition of data, analysis or interpretation of data, drafting/revising the manuscript, critical revision of the manuscript for important intellectual content, study supervision.

Study funding

This practice guideline was developed with financial support from the American Academy of Neurology (AAN). Authors who serve as AAN subcommittee members or as methodologists (A.R.-G., G.S.D., A.R., G.S.G., M.H., S.P., T.P.), or who are or were AAN staff members (T.S.D.G., S.A.M.), were reimbursed by the AAN for expenses related to travel to subcommittee meetings where drafts of manuscripts were reviewed. All authors on the panel were reimbursed by the AAN for expenses related to travel to 2 in-person meetings.

Disclosure

A. Rae-Grant receives royalties from 2 textbooks he has published, 1 on neurology and 1 on multiple sclerosis (MS); organizes and receives honoraria for grand rounds and neurology review courses; and is local primary investigator for a clinical trial with MedDay Pharmaceuticals, for which he receives no personal compensation. A. Rabinstein reports no disclosures relevant to the manuscript. B. Cree has received compensation for consulting from AbbVie, Biogen, EMD Serono, GeNeuro, Genzyme/Sanofi Aventis, Novartis, and Shire; has given expert testimony and prepared an affidavit for medical malpractice cases (1 or 2 per year) within his area of expertise; and has acted as consultant in a legal proceeding for Acorda and Biogen. G. Gronseth serves as associate editor (level of evidence review) for Neurology®; serves on the editorial advisory board for Neurology Now; and is compensated by the American Academy of Neurology (AAN) for methodologic activities. G. Day holds stock in ANI Pharmaceuticals. M. Haboubi has received travel reimbursement and honoraria for grand rounds presentations in Madisonville, KY. J. Halper and J. Hosey report no disclosures relevant to the manuscript. D. Jones has received personal compensation for consulting from Biogen and Genzyme; has received honoraria from the Consortium of Multiple Sclerosis Centers (CMSC), the Multiple Sclerosis Association of America (MSAA), and the Pharmacy Quality Alliance; has received institutional research support from Biogen and the National MS Society (NMSS); has received salary support from the CMSC; and has received travel reimbursement from Biogen and Genzyme and from the AAN, Can Do MS, the CMSC, and the MSAA. R. Lisak served as the President of the CMSC and serves as a member of the Board of the DMC Foundation; has served on scientific advisory boards for Mallinckrodt, Syntimmune, Celegene, and Alexion; serves as chair of the adjudication committee of a clinical trial (PAREXEL); has received funding for travel from the CMSC, the GBS/CIDP Foundation International, the NMSS, and Syntimmune for travel to consultants meetings; has served as a journal editor for Clinical and Experimental Neuroimmunology and Clinical Neuropharmacology; has received publishing royalties from Willey for International Neurology, A Clinical Approach; has received honoraria from Mallinckrodt, Syntimmune, and Teva Pharmaceuticals, and from the consulting agencies AlphaSights, ClearView Healthcare Partners, GLC, and Insights Consulting; has served on a speakers bureau for Teva Pharmaceuticals for talks unrelated to pharmaceuticals; has received research support from Mallinckrodt for investigator-initiated wet bench studies, and from Acorda, Avanir, Biogen, Chugai, Genentech, MedImmune, Novartis, and Teva Pharmaceuticals for serving as a site investigator in multicenter trials; has given expert testimony, prepared an affidavit and acted as witness for Teva Pharmaceuticals; and has acted as an expert on a patent case for Acorda. Wayne State University has received financial compensation from the NMSS for his salary as principle investigator for a research grant. R.A. Marrie receives research grants from nonprofit organizations, including Canadian Institutes of Health Research (CIHR), the CMSC, Crohn's and Colitis Canada, the NMSS, the Multiple Sclerosis Society of Canada, the Multiple Sclerosis Scientific Research Foundation, and Research Manitoba; and serves on the editorial board of Neurology. D. Pelletier has served on scientific advisory boards for Biogen, EMD Serono, Genzyme/Sanofi Aventis, Hoffman LaRoche, and Novartis; has received research support for Biogen, Genzyme, Hoffman LaRoche, and the National Institute of Neurologic Disorders and Stroke of the NIH; and has received honoraria for providing consulting services at scientific advisory board meetings from Biogen, EMD Serono, Genzyme/Sanofi Aventis, Hoffman LaRoche, and Novartis. S. Potrebic received an honorarium from CDI Quality Institute PLE for participation in a headache appropriate-use criteria panel for imaging; and receives travel reimbursement from the AAN for attending AAN Residency In-Service Training Examination Work Group meetings, AAN Axon Registry Committee meetings, AAN Guideline Development, Dissemination, and Implementation Subcommittee meetings, and the Guidelines International Network North America Evidence-based Guidelines Affecting Policy, Practice, and Stakeholders (E-GAPPS) conference. R. Sommers, C. Sitcov, and J. Stachowiak report no disclosures relevant to the manuscript. T. Getchius is a former AAN employee and reports no relevant disclosures. S. Merillat reports no disclosures relevant to the manuscript. T. Pringsheim has received research support from the CIHR and Shire Canada Inc. Go to http://n.neurology.org/lookup/doi/10.1212/WNL.0000000000005345 for full disclosures.

Disclaimer

Clinical practice guidelines, practice advisories, systematic reviews, and other guidance published by the American Academy of Neurology and its affiliates are assessments of current scientific and clinical information provided as an educational service. The information (1) should not be considered inclusive of all proper treatments, methods of care, or as a statement of the standard of care; (2) is not continually updated and may not reflect the most recent evidence (new evidence may emerge between the time information is developed and when it is published or read); (3) addresses only the question(s) specifically identified; (4) does not mandate any particular course of medical care; and (5) is not intended to substitute for the independent professional judgment of the treating provider, as the information does not account for individual variation among people with MS. In all cases, the selected course of action should be considered by the treating provider in the context of treating the individual patient. Use of the information is voluntary. AAN provides this information on an “as is” basis, and makes no warranty, expressed or implied, regarding the information. AAN specifically disclaims any warranties of merchantability or fitness for a particular use or purpose. AAN assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this information or for any errors or omissions.

Conflict of interest statement

The American Academy of Neurology (AAN) is committed to producing independent, critical, and truthful clinical practice guidelines (CPGs). Significant efforts are made to minimize the potential for conflicts of interest to influence the recommendations of this CPG. To the extent possible, the AAN keeps separate those who have a financial stake in the success or failure of the products appraised in the CPGs and the developers of the guidelines. Conflict of interest forms were obtained from all authors and reviewed by an oversight committee prior to project initiation. AAN limits the participation of authors with substantial conflicts of interest. The AAN forbids commercial participation in, or funding of, guideline projects. Drafts of the guideline have been reviewed by at least 3 AAN committees, a network of neurologists, Neurology® peer reviewers, and representatives from related fields. The AAN Guideline Author Conflict of Interest Policy can be viewed at aan.com. For complete information on this process, access the 2011 AAN process manual, as amended.4

Acknowledgment

The authors thank the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry for its assistance in administering an outcomes survey, the results of which were included in this practice guideline. NARCOMS is supported in part by the Consortium of Multiple Sclerosis Centers (CMSC) and the Foundation of the CMSC.

Footnotes

  • Go to http://n.neurology.org/lookup/doi/10.1212/WNL.0000000000005345 for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Approved by the Guideline Development, Dissemination, and Implementation Subcommittee on October 9, 2017; by the AAN Practice Committee on October 21, 2017; and by the AAN Institute Board of Directors on March 6, 2018.

  • Editorial, page 761

  • See page 777

  • Practice Guidelines NPub.org/77nyxt

  • Received July 12, 2017.
  • Accepted in final form February 15, 2018.

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