AAN Releases New Practice Guideline on Disease-Modifying Therapies for Multiple Sclerosis

When Cleveland Clinic neurologist Alexander Rae-Grant, MD, unveiled the new American Academy of Neurology (AAN) practice guideline on disease-modifying therapies (DMTs) for adults with multiple sclerosis (MS) at the AAN annual meeting April 23, there was plenty to cover.

Large amounts of research have been published since the previous AAN guideline on the subject was issued in 2002, and the new recommendations are the culmination of a systematic review of the literature and other evidence by a panel of physicians, nurses and patients from the U.S. and Canada.

Consult QD sat down with Dr. Rae-Grant, who led the review process and guideline development, to learn key takeaways from the guideline and get a behind-the-scene glimpse of the undertaking. The full guideline was simultaneously published in Neurology.

Q: To start, was there something noteworthy about the process of creating this guideline?

A: Some guidelines rely heavily on expert opinion. That was not the case here: Ours was a much more transparent and systematic process that stuck closely to the evidence. We strictly followed all the recommendations issued by the Institute of Medicine (now the National Academy of Medicine) for developing evidence-based guidelines. Each guideline recommendation is accompanied by a summary of the rationale used to come to a decision and a letter grade indicating the strength of the evidence. We had about as tight a process as possible, so I feel comfortable with our recommendations.

We also incorporated patient preferences in formulating recommendations, by relying on a survey of more than 5,000 people from the North American Research Committee on Multiple Sclerosis Registry. The survey solicited opinions on lifestyle priorities and the importance of various clinical outcomes, including those related to the safety and tolerability of medications. Shared decision-making is especially important in a disease such as MS, which involves considerable variability of treatment risks and benefits and disease course.

Q: Thirty recommendations were developed. What are some of the key ones?

A: Seventeen recommendations concern initiating therapy. Among these, a few should be highlighted:

• Clinicians should counsel patients that DMTs are prescribed to try to slow long-term progression of disability, not to control immediate symptoms.
• DMTs are recommended for patients with a single clinical demyelinating event and two or more brain lesions characteristic of MS. These criteria do not meet the 2010 International Criteria for MS, but evidence shows that DMTs are associated with a significant delay in development of MS in this setting.
• For patients with a clinically isolated syndrome or a relapsing form of MS who do not choose to take a DMT, serial MRI is recommended at least annually so that a change in disease activity can be detected that might change the treatment strategy.
• Use of alemtuzumab, fingolimod or natalizumab is recommended for highly active MS.
• Ocrelizumab is recommended for patients with primary progressive MS who are ambulatory.

Ten recommendations deal with switching DMTs, which is a dilemma faced if it’s suspected that the current drug is not as effective as it should be. Clinicians should monitor MRI disease activity from the clinical outset to detect disease progression and inform treatment decisions. For a patient who has been using a DMT long enough for it take full effect, criteria for determining when to switch are any of the following over a one-year period of use:

• One or more clinical relapses
• Two or more unequivocally new MRI-detected lesions
• Increased disability on examination

Three recommendations are devoted to stopping DMT. No good evidence is available that addresses whether, when or why to discontinue DMTs in a patient with relapsing-remitting MS who has no evidence of progression. Sometimes a third party, such as an insurer or health plan, may become involved in decisions about specific medications allowed. In such cases, clinicians should serve as an advocate for the patient as well as for the principle that only patients and doctors should determine appropriate therapy.

Finally, a controversial recommendation was that clinicians may advise discontinuing DMT for people with secondary progressive MS without ongoing relapses and who have not been ambulatory for at least two years. For such patients, disease activity is likely limited and the benefit of continued therapy low.

Q: Was there anything else controversial or surprising that you can share?

A: I was surprised that so many things I thought would not be controversial turned out to be! We took our mandate to keep to the evidence very seriously. We only recommended drugs for which we had evidence of benefit; if there were others in the same class with lack of supportive evidence, we did not include them in the recommendations. Understandably, proponents of some drugs did not always take the omission of those drugs lying down.

We did not address the hot topic in the field right now of so-called highly effective early treatment — i.e., using the strongest drugs up front, rather than the traditional approach of starting with the least toxic, standard medication and progressively increasing the strength and risk of therapy. The evidence for which strategy is better is not yet in, but it should be soon. This will certainly be addressed in the next guideline.