Time Matters in MS: Expert Q&A With Alexander Rae-Grant, MD

In April 2018, the American Academy of Neurology released updated guidelines for the treatment of multiple sclerosis (MS).¹ The new recommendations are based on a panel review of 20 Cochrane reviews and 73 full-text articles pertaining to starting, switching, and stopping disease-modifying treatment (DMT) in patients with clinically isolated syndrome, relapsing-remitting MS (RRMS), and progressive forms of MS. Since the publication of the previous guidelines in 2002, treatment options have improved and expanded significantly.

The updated recommendations reflect an increased awareness of the importance of early treatment in MS, based on research demonstrating benefits in terms of slowing disease progression and resulting neurological damage. For example, a study published in 2017 in Multiple Sclerosis (N=639) found a greater risk of reaching a score of 4 on the Expanded Disability Status Scale among patients initiated on treatment later in the disease course (hazard ratio, 1.074; 95% CI, 1.048-1.101).²

The risk increased by 7.4% for each year of delayed treatment after the onset of MS. Compared with patients who initiated treatment within 1 year of onset, those who initiated treatment 3 years after onset reached Expanded Disability Status Scale 4 sooner (hazard ratio, 2.64; 95% CI, 1.71-4.08).

In addition, recent findings suggest that the efficacy of DMTs may decrease with age, which if confirmed, would further highlight the need for early treatment initiation. In a meta-analysis of randomized clinical trials with a combined total of 28,000 patients, researchers at the National Institute of Neurological Disorders and Stroke and the National Institutes of Health observed a substantial decline in DMT efficacy until age 53 years (R² = 0.6757; P =6.39e−09), and subsequently there appeared to be no therapeutic benefit. The results also indicated that patients younger than 40.5 years experienced a greater therapeutic benefit from drugs classified as high efficacy vs low efficacy.

Taken together, such findings indicate that timing is a critical consideration in MS treatment, potentially throughout the lifespan. To further explore this theme, Neurology Advisor spoke with Alexander Rae-Grant, MD, a neurologist at Cleveland Clinic and lead author of the new guidelines.

Neurology Advisor: Generally, what is new in the updated guideline for MS treatment?

Dr Rae-Grant: This guideline addresses new information on 23 medications that modify disease activity in MS. In addition, it reviews treatment for patients with a first episode of demyelination who do not yet have MS but are at high risk. The guideline focuses on incorporating patient preferences and specific conditions into the decision to treat and which medication to use. It emphasizes the need for careful monitoring for adherence to medication as well as adverse effects. 

Neurology Advisor: What is known about the importance of early treatment in MS?

Dr Rae-Grant: We now have multiple studies showing that treatment even after only 1 relapse and before diagnosis of MS reduces the risk for further relapses, the risk for new lesions on MRI, and the risk of progressing to a diagnosis of MS. We know that once lesions have formed, they will usually not disappear, and that this is part of the cause of long-term disability. So, early treatment that reduces new lesion development increases the chance that in the long term, patients will do better with their MS. 

Neurology Advisor: What does the evidence suggest about MS treatments becoming less effective later in life?

Dr Rae-Grant: I would not say that they become less effective later in life. What we know about the natural history of MS is that relapses tend to be more common early in the course of the condition, new magnetic resonance imaging lesions are more common early in the course, and both are less frequent over the years of the illness. So, it is really later in the course of MS that the medicines are less effective, not specifically related to age. If people have relapses or magnetic resonance imaging new lesion activity, treatment with DMT is appropriate at any age, depending on other specific health conditions the person with MS may also have.

Neurology Advisor: What should be the focus of future research in this area?

Dr Rae-Grant: Certainly, we would love to have medicines that protect or repair the injured nervous system, and this is an active focus of basic research. In the near future, studies that are now enrolling to compare the effect of different medicines in the clinical population and studies to see whether a more effective treatment given earlier is better than standard care will help us do a better job treating the population with MS.

References

1. Rae-Grant A, Day GS, Marrie RA, et al. Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90(17):777-788.
2. Kavaliunas A, Manouchehrinia A, Stawiarz L, et al. Importance of early treatment initiation in the clinical course of multiple sclerosis. Mult Scler. 2017;23(9):1233-1240.
3. Weideman AM, Tapia-Maltos M, Johnson K, Greenwood M, Bielekova B. Meta-analysis of the age-dependent efficacy of multiple sclerosis treatments.Front Neurol. 2017;8:577.