New AAN Guidelines Advocate Early MS Treatment

Susan Jeffrey

April 23, 2018

LOS ANGELES — New guidelines on the use of disease-modifying therapies (DMTs) in patients with multiple sclerosis (MS) provide updated guidance on starting, switching, and stopping treatment and recommend an earlier start to treatment rather than later in the disease course.

The guidelines are published online April 23 in Neurology as two documents: the practice guidelines recommendations summary and the comprehensive systematic review summary outlining the evidence supporting them.

The recommendations, which apply to patients with relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS) and those with clinically isolated syndrome (CIS) of demyelination, were presented here at the American Academy of Neurology (AAN) 2018 Annual Meeting. They are endorsed by the Multiple Sclerosis Association of America and the National Multiple Sclerosis Society.

"The treatment landscape for people with multiple sclerosis has changed dramatically in the past decade," lead author, Alexander Rae-Grant, MD, professor of medicine (neurology) at the Cleveland Clinic Lerner College of Medicine, Ohio, said at a press conference here. "We now have many disease-modifying therapies from which to choose."  

The last guideline was published in 2002, and since a variety of treatments have been approved, as well as others used off label, he noted. Furthermore, treatments vary by effectiveness, safety, and route of administration, and this "makes life very hard in terms of making decisions."

For the guideline, a multidisciplinary panel used findings from the systematic review of the literature and followed an National Academy of Medicine –compliant process to developed modified Delphi consensus-based recommendations on starting, switching, and stopping the variety of DMTs now available.

Among these is an endorsement for clinicians to discuss prescribing DMT to patients with a single clinical demyelinating event and two or more brain lesions characteristic of MS, that is, patients early in the disease course.

Dr Alexander Rae-Grant (left) and Dr Ruth Ann Marrie (right)

"We found that for most people it is better to start taking drugs for multiple sclerosis early on, rather than letting the disease run its course," said Ruth Ann Marrie, MD, PhD, professor in the Department of Internal Medicine (Neurology) and the Department of Community Health Sciences at the University of Manitoba, Winnipeg, Canada, and director of the Multiple Sclerosis Clinic, a coauthor of the guideline during the press conference. "According to this guideline, several drugs have either strong or moderate evidence supporting their use for slowing certain disease processes."

Other recommendations look at strategies to engage patients in these decisions and individualization of treatment, including monitoring treatment adherence, and assessment of comorbidities. While they didn't formally look at the costs of treatment, Marrie noted, "there is a specific recommendation within the guideline that allows for people who may not have access for financial reasons to some of the therapies to consider off-label use of a couple of medications, specifically azathioprine and cladribine."

"The guideline also points clinicians to think about some of the sources where patients might be able to get financial assistance with access to medications, recognizing that this is a substantial concern for many with MS," she added.

The authors also review the risks of treatment, including counseling on the risk for progressive multifocal leukoencephalopathy (PML) with natalizumab, fingolimod, rituximab, ocrelizumab, and dimethyl fumarate. 

In all, 30 recommendations were developed: 17 on starting DMTs, 10 on switching from one therapy to another if breakthrough disease develops, and 3 on considerations related to stopping therapy. The recommendations include the following:

Starting DMTs

  1. Clinicians should counsel people with newly diagnosed MS about specific treatment options with DMT at a dedicated treatment visit. Level B

  2. Clinicians must ascertain and incorporate/review preferences in terms of safety, route of administration, lifestyle, cost, efficacy, common adverse effects (AEs), and tolerability in the choice of DMT in people with MS being considered for DMT. Clinicians must engage in an ongoing dialogue regarding treatment decisions throughout the disease course with people with MS. Level A

  3. Clinicians should counsel people with MS that DMTs are prescribed to reduce relapses and new MRI lesion activity. DMTs are not prescribed for symptom improvement in people with MS. Level B

  4. Clinicians must counsel people with MS on DMTs to notify the clinicians of new or worsening symptoms. Level A

  5. Clinicians should evaluate readiness or reluctance to initiate DMT and counsel on its importance in people with MS who are candidates to initiate DMT. Level B

  6. Clinicians should counsel about comorbid disease, adverse health behaviors, and potential interactions of the DMT with concomitant medications when people with MS initiate DMTs. Level B

  7. Clinicians should evaluate barriers to adherence to DMT in people with MS. Clinicians should counsel on the importance of adherence to DMT when people with MS initiate DMTs. Level B

  8. Clinicians should discuss the benefits and risks of DMTs for people with a single clinical demyelinating event with two or more brain lesions that have imaging characteristics consistent with MS. After discussing the risks and benefits, clinicians should prescribe DMT to people with a single clinical demyelinating event and two or more brain lesions characteristic of MS who decide they want this therapy. Level B

  9. Clinicians may recommend serial imaging at least annually for the first 5 years and close follow-up rather than initiating DMT in people with CIS or relapsing forms of MS who are not on DMT, have not had relapses in the preceding 2 years, and do not have active new MRI lesion activity on recent imaging. Level C

  10. Clinicians should offer DMTs to people with relapsing forms of MS with recent clinical relapses or MRI activity. Level B

  11. Clinicians should monitor for medication adherence, AEs, tolerability, safety, and effectiveness of the therapy in people with MS on DMTs. Clinicians should follow up either annually or according to medication-specific REMs in people with MS on DMTs. Level B

  12. Clinicians should monitor the reproductive plans of women with MS and counsel regarding reproductive risks and use of birth control during DMT use in women of childbearing potential who have MS. Level B

  13. Clinicians should counsel men with MS on their reproductive plans regarding treatment implications before initiating treatment with teriflunomide or cyclophosphamide. Level B

  14. Because of the high frequency of severe AEs, clinicians should not prescribe mitoxantrone to people with MS unless the potential therapeutic benefits greatly outweigh the risks. Level B

  15. Clinicians should prescribe alemtuzumab, fingolimod, or natalizumab for people with MS with highly active MS. Level B

  16. Clinicians may direct people with MS who are candidates for DMTs to support programs. Clinicians may recommend azathioprine or cladribine for people with relapsing forms of MS who do not have access to approved DMTs. Level C

  17. Clinicians may initiate natalizumab treatment in people with MS with positive anti-JCV antibody indexes above 0.9 only when there is a reasonable chance of benefit compared with the low but serious risk of PML. Level C

  18. Clinicians should offer ocrelizumab to people with PPMS who are likely to benefit from this therapy unless there are risks of treatment that outweigh the benefits. Level B

Switching DMTs 

  1. Clinicians should monitor MRI disease activity from the clinical onset of disease to detect the accumulation of new lesions in order to inform treatment decisions in people with MS using DMTs. Clinicians should recognize that relapses or new MRI-detected lesions may develop after initiation of a DMT and before the treatment becomes effective in people with MS who are using DMTs. Clinicians should discuss switching from one DMT to another in people with MS who have been using a DMT long enough for the treatment to take full effect and are adherent to their therapy when they experience one or more relapses, two or more unequivocally new MRI-detected lesions, or increased disability on examination, over a 1-year period of using a DMT. Level B

  2. Clinicians should evaluate the degree of disease activity, adherence, AE profiles, and mechanism of action of DMTs when switching DMTs in people with MS with breakthrough disease activity during DMT use. Level B

  3. Clinicians should discuss a change to noninjectable or less frequently injectable DMTs in people with MS who report intolerable discomfort with the injections or in those who report injection fatigue on injectable DMTs. Level B

  4. Clinicians should inquire about medication AEs with people with MS who are taking a DMT and attempt to manage these AEs, as appropriate. Clinicians should discuss a medication switch with people with MS for whom these AEs negatively influence adherence. Level B

  5. Clinicians should monitor laboratory abnormalities found on requisite laboratory surveillance (as outlined in the medication's package insert) in people with MS who are using a DMT. Clinicians should discuss switching DMT or reducing dosage or frequency (where there are data on different doses [eg, interferons, teriflunomide, azathioprine]) when there are persistent laboratory abnormalities. Level B

  6. Clinicians should counsel people with MS considering natalizumab, fingolimod, rituximab, ocrelizumab, and dimethyl fumarate about the PML risk associated with these agents. Clinicians should discuss switching to a DMT with a lower PML risk with people with MS taking natalizumab who are or become JCV antibody positive, especially with an index of above 0.9 while on therapy. Level B

  7. Clinicians should counsel that new DMTs without long-term safety data have an undefined risk of malignancy and infection for people with MS starting or using new DMTs. If a patient with MS develops a malignancy while using a DMT, clinicians should promptly discuss switching to an alternate DMT, especially for people with MS using azathioprine, methotrexate, mycophenolate, cyclophosphamide, fingolimod, teriflunomide, alemtuzumab, or dimethyl fumarate. People with MS with serious infections potentially linked to their DMT should switch DMTs (does not pertain to PML management in people with MS using DMT). Level B

  8. Clinicians should check for natalizumab antibodies in people with MS who have infusion reactions before subsequent infusions, or in people with MS who experience breakthrough disease activity with natalizumab use. Clinicians should switch DMTs in people with MS who have persistent natalizumab antibodies. Level B

  9. Physicians must counsel people with MS considering natalizumab discontinuation that there is an increased risk of MS relapse or MRI-detected disease activity within 6 months of discontinuation. Level A

  10. Physicians and people with MS choosing to switch from natalizumab to fingolimod should initiate treatment within eight to 12 weeks after natalizumab discontinuation (for reasons other than pregnancy or pregnancy planning) to diminish the return of disease activity. Level B

  11. Clinicians should counsel women to stop their DMT before conception for planned pregnancies unless the risk of MS activity during pregnancy outweighs the risk associated with the specific DMT during pregnancy. Clinicians should discontinue DMTs during pregnancy if accidental exposure occurs, unless the risk of MS activity during pregnancy outweighs the risk associated with the specific DMT during pregnancy. Clinicians should not initiate DMTs during pregnancy unless the risk of MS activity during pregnancy outweighs the risk associated with the specific DMT during pregnancy. Level B

Stopping DMTs

  1. In people with RRMS who are stable on DMT and want to discontinue therapy, clinicians should counsel people regarding the need for ongoing follow-up and periodic reevaluation of the decision to discontinue DMT. Clinicians should advocate that people with MS who are stable (that is, no relapses, no disability progression, stable imaging) on DMT should continue their current DMT unless the patient and physician decide a trial off therapy is warranted. Level B

  2. Clinicians should assess the likelihood of future relapse in individuals with SPMS by assessing patient age, disease duration, relapse history, and MRI-detected activity (eg, frequency, severity, time since most recent relapse or gadolinium-enhanced lesion). Level B

  3. Clinicians may advise discontinuation of DMT in people with SPMS who do not have ongoing relapses (or gadolinium-enhanced lesions on MRI activity) and have not been ambulatory (EDSS [Expanded Disability Status  Scale] 7 or greater) for at least 2 years. Level C

  4. Clinicians should review the associated risks of continuing DMTs versus those of stopping DMTs in people with CIS using DMTs who have not been diagnosed with MS. Level B

"This guideline reflects the complexity of decision-making for starting, switching, or stopping MS DMTs," the authors conclude. "The field of MS treatment is rapidly changing; the Academy of Neurology development process includes planning for future updates."

Specific questions for future research include the comparisons of strategies for treatment, Rae-Grant noted, "particularly comparisons of strategies for treatment; a strategy of starting with low-risk, maybe lower efficacy drugs versus strongest, most robust medication initially, that really hasn't been well-studied before; comparative effectiveness research, in terms of comparing different drugs in the marketplace."

Other open questions include optimal switching strategies, long-term effects of DMT, definitions of "highly active" MS, and effects of treatment on "patient-specific priority outcomes."

At the press conference here, the authors were asked how these guidelines differ from those of the European Committee for Research and Treatment of Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN), presented at the October 2017 ECTRIMS meeting and published in January in the.

Marrie pointed to several differences not only in the recommendations but also the process of coming to recommendations between the guidelines, as well as differences in the regulatory environments between the United States and Europe.

Still, she said, "in broad strokes, I think the guidelines share some strong similarities in terms of the recommendations for early use of disease-modifying therapy, maintaining therapy in terms of individuals who are responding well to therapy, and recommending switches of therapy in individuals who appear not to be responding on the basis of, for instance, breakthrough relapse and changes on MRI."

There are, she added, "some slight differences in tone around some specific medications, such as mitoxantrone, for example, where there is a bit more concern in our guideline regarding the safety of that medication and its use, and I think there are some differences as well in terms of recommendations around pregnancy where the AAN guideline is more conservative in some of those strategies.

"But I think to a large degree, beyond some methodological differences, any differences that arise here reflect gaps in knowledge where there is some decision that has to be made about interpretation of recommendations in the absence of available evidence that we would like."

Complexity of Disease

An accompanying editorial was coauthored by Tanuja Chitnis, MD, from Partners Multiple Sclerosis Center, Brigham and Women's Hospital, Boston, Massachusetts; Gavin Giovannoni, MD, from Barts and The London School of Medicine and Dentistry, Queen Mary University London, United Kingdom; and Maria Trojano, MD, from the University of Bari, Italy.

In it, they point out that "prodigious progress in the treatment of multiple sclerosis has occurred over the last 20 years, with the licensing of more than 15 novel and highly effective disease-modifying therapies to treat the disease."

"In this new complex scenario, an update of the previous therapeutic guidelines published by the American Academy of Neurology in 2002 is needed for an appropriate and effective use of new and old agents in clinical practice," they write.

They too point to areas where further research is need. For example, a clear definition of SPMS is "lacking." Delayed risks and long-term benefits of many of the current DMTs "have not been assessed," and "good-quality real-world observational studies with sufficiently long follow-up may address some of these issues."

Also required are guidance to identify radiologically isolated syndrome, or CIS cases at risk for transitioning to MS, and studies to provide data on when it's safe to stop treatment and in which populations, "particularly in the aging population, in whom long-term immunomodulation could have adverse effects," they write.

"The MS field is sorely in need of validated predictive biomarkers and algorithms that will identify patients at high risk for more aggressive disease, and, therefore, who would be appropriate for more effective early treatments," they noted.

"At present, these determinations are made by the experienced MS clinician, who is needed to help guide patients through this complex landscape," the editorialists conclude. "The revised AAN guidelines are a starting point for the use of the multiple treatments now available for MS; however, further work is needed to further refine the choices appropriate for the individual patient."

The practice guideline was developed with financial support from the AAN. Authors who serve as AAN subcommittee members or as methodologists, or who are or were AAN staff members, 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 two in-person meetings. The AAN discloses that it is "committed to producing independent, critical, and truthful clinical practice guidelines" and that "significant efforts are made to minimize the potential for conflicts of interest to influence the recommendations" of this guideline. "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."  Rae-Grant reports he receives royalties from two textbooks he has published: one on neurology and one on MS; organizes and receives honoraria for ground rounds and neurology review courses; and is local primary investigator for a clinical trial with MedDay Pharmaceuticals, for which he receives no personal compensation. Marrie reports she receives research grants from nonprofit organizations, including Canadian Institutes of Health Research, the Consortium of Multiple Sclerosis Centers , Crohn's and Colitis Canada, the National Multiple Sclerosis Society , the Multiple Sclerosis Society of Canada, the Multiple Sclerosis Scientific Research Foundation, and Research Manitoba; and serves on the editorial board of Neurology. Chitnis has served on scientific advisory boards for Biogen, Celgene, Novartis, and Sanofi-Genzyme. She has received research grants for her institution from Octave, Serono, and Verily. Giovannoni has served on advisory boards for AbbVie, Atara Bio, Biogen, Genzyme, Genentech, GlaxoSmithKline, Merck-Serono, Novartis, Roche, Sanofi-Genzyme, Synthon BV, and Teva Pharmaceutical Industries. Trojano has served on scientific advisory boards for Biogen, Novartis, Almirall, Roche, and Genzyme; has received speaker honoraria from Biogen Idec, Bayer Schering, Sanofi-Aventis, Merck Serono, Teva, Genzyme, Almirall, and Novartis; and has received research grants for her institution from Biogen Idec, Merck Serono, and Novartis.

Neurology. 2018;90:777-788, 789-800, 761-762.  Published online April 23, 2018. Guideline summary, Systematic review, Editorial

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