• Gary Birnbaum, MD

A Reasonable Approach to the Treatment of MS

Improving quality, affordability, and equity of multiple sclerosis care

Annette Langer-Gould, Shilpa Klocke, Brandon Beaber, Sonu M. Brara, Julie Debacker, Oluwasheyi Ayeni & Allen S. Nielsen

Annals of Clinical and Translational Neurology 2021; 8(4): 980–991


Treatment of multiple sclerosis, algorithm of MS treatment, Therapy of MS, Choosing MS treatments, When and how to treat MS, Risk stratified approach to the treatment of MS
Figure #1: Who to treat and how

Bottom Line:

Many disease-modifying therapies are available to health care providers to treat relapsing forms of multiple sclerosis. While this is clearly beneficial it also has resulted in questions and confusion, especially among providers not specializing in the treatment of persons with MS. Who should be treated? Which drugs are best for an individual? When should treatment be changed and when can it be stopped? What is the cost-effectiveness of the drugs, since most are very expensive, and co-pays may prevent access to some therapies?

The authors of the above paper noted a great disparity in the use of disease-modifying therapies in persons with relapsing forms of multiple sclerosis. They noted that use of highly effective treatments in persons with very aggressive MS was underutilized, often because of health care providers’ concerns about drug toxicity and lack of familiarity with alternatives. Treatment was often withheld due to costs of drug co-pays or restrictions on access to therapies based on insurance company formularies.

The above paper addresses these issues and proposes science-based algorithms to provide health care providers with a uniform and maximally beneficial approach. Using clinical and imaging criteria Individuals with MS are first ranked in terms of their risk of developing rapid and disabling disease. Disease-modifying therapies are also ranked based on their effectiveness in controlling disease, their potential for adverse reactions and their costs. Recommendations are then made regarding which therapies should be tried initially as well as recommendations in instances of breakthrough disease or intolerable side-effects.

The algorithms discussed in this paper should allow persons with MS to receive treatment individualized to their pattern of illness, with an appropriate balance of risks and benefits, in a more uniform pattern, even when care is given by providers without special expertise in the treatment of multiple sclerosis.

Stratifying risk for multiple sclerosis disease progression, Who is a risk for more severe MS?, Choosing disease-modifying therapies  based on risks for more severe multiple sclerosis, Risk assessment for more severe MS,
Figure #2: Who may be at risk for more severe MS?

Key Points:

1. The course of MS varies greatly. Some persons develop severe disability shortly after onset of their illness while others note only minimal changes decades after diagnosis.

2. There are no absolute ways to predict how a person’s MS will progress. There are, however, some features of a person’s illness that increase the risks for more severe disease. These include male sex, numbers of relapses, poor recovery from relapses, involvement of the motor and cerebellar systems, spinal cord involvement, numbers of lesions on central nervous system MRIs especially “black holes,” and loss of brain tissue or atrophy. Using such criteria, the authors of the above paper advised ranking persons with MS based on their risks for more severe disease.

3. The authors than categorized the multitude of disease-modifying therapies currently available based on their published effectiveness in suppressing MS. Three categories of effectiveness were defined, highly effective treatments (HETs), such as rituximab and natalizumab, moderately effective treatments (meDMTs), and drugs of low or uncertain effectiveness.

4. HETs, while potent and able to suppress disease, also have an increased risk of adverse events. These include an increased risks of infection and malignancy, organ damage, other autoimmune diseases and bone-marrow suppression. Thus, in choosing a disease-modifying therapy the risks must be balanced against potential benefits.

5. For persons at low risk for rapid disease progression the authors suggested meDMTs but with induction therapy. Induction therapy involves treatment with a HET for a short time at onset of disease, then switching to a possibly less effective, but also less potentially toxic drug thereafter. Use of only low or possibly ineffective medications at onset of treatment were not recommended since if disease activity recurred, it would be unclear whether a HET or meDMT was needed. Figure 2 is their schema for stratifying individuals.

6. The authors advised choosing the safest drug in each category. Multiple criteria were used, among them the drug least likely to cause adverse events should switching to another disease-modifying therapy be needed, the drug with least complexity of use regarding the need for repeated testing and evaluations, a drug that minimizes the risks of rebound disease should treatment need to be stopped, and a drug with least potential to affect pregnancy outcomes. Finally, the lowest cost drug in each category was considered, but costs did not affect which category of drug to use or to compromise the choice if the drug’s safety profile as not acceptable.

7. The authors’ algorithms for treatment are detailed in their Figure 1 (shown at the top of this posting). Their choices of disease-modifying therapies, based on the above criteria, are the HETs rituximab and natalizumab. Their choices of meDMTs are interferon-beta and glatiramer acetate. Oral agents are not the authors’ first choices, even if costs are low, due to increased risks of toxicities with the oral agents and the risks of disease rebound with several of the drugs should a change in treatment be needed. If injectable meDMTs are not tolerated, switching to either natalizumab or rituximab is suggested.

8. The authors do recommend induction therapy with rituximab in moderate or low risk persons with MS prior to switching to a meDMT. While data in support of such an approach are limited, the authors felt this would maximize the response to the meDMT.

9. The authors recommend a goal of having 60-70% of persons with MS on a HET, given that this proportion of individuals will have clinically significant disability after 20 years of illness.

10. Careful follow-up every three months is essential to assess treatment effectiveness and to recommend changes as soon as needed.

11. Finally, the authors advise caution in using high-risk HETs in older persons with progressive disease with no acute inflammation, since such drugs may have little if any benefit, and risks may be substantially greater. Indeed, if no acute inflammation is noted, disease-modifying therapy can be stopped.

12. The authors state that use of their algorithms has resulted in better patient care with less toxicities, better affordability, and good disease control.


The availability of multiple disease-modifying therapies for treatment of relapsing forms of multiple sclerosis has benefited many persons with MS. However, there is a downside. Health care providers not experienced in the care of persons with MS may have difficulty in choosing the best drug for an individual or may have amplified concerns about potential drug toxicity such that an appropriate medication is not recommended. In addition, identifying insufficient treatment response may be difficult, resulting in a delay when a change of treatment is needed. The authors of the above paper noted these issues in their clinics and proposed a series of algorithms to address them.

Their approach was two-fold. First, they categorized persons with MS regarding their risks for developing increasing disability. There are no absolute ways of assessing risks of disease progression but there are features of MS that are associated with a more disabling course. These include male sex, frequent relapses with incomplete recovery, involvement of motor and cerebellar systems, and spinal cord involvement.

The authors then ranked disease-modifying therapies into high efficacy treatments (HETs) and medium effective disease-modifying therapies (meDMTs). Multiple criteria were used. First, was the ability of a medication to control disease, especially if the trial compared the medication to another active treatment and was superior. Second was the short term and long-term safety and potential toxicity of the drug with an assessment of the risks of taking the drug in relation to its potential benefit. Finally, was the cost of the drug, as cost-sharing for some treatments may be unaffordable to a large segment of persons with MS.

In persons with low risks for severe disease the authors recommended initial, “induction” treatment with the HET rituximab for several months, followed by one of the injectable medications, either one of the interferon-betas or glatiramer acetate. Persons categorized as high risk for a disabling course of MS were advised to start initial therapy with an HET, either rituximab or natalizumab. Other HETs such as ocrelizumab, ofatumumab, alemtuzumab and cladribine were not advised due to insufficient evidence that these were more effective than rituximab and natalizumab, the increased risks of adverse events with these drugs, and their greater costs.

Close follow-up was also advised, with quarterly visits to assess disease activity. Should persons on meDMTs experience new disease activity, rapid switching to a HET was advised. The authors also noted that all disease-modifying therapies lose their effectiveness in older persons with MS, especially those with progressive disease and no evidence of acute inflammation. Risks for adverse reactions to disease-modifying therapies also increase with age. Thus, stopping disease-modifying therapy in older individuals with progressive disease and no evidence of acute inflammation was suggested.

Some of the authors’ recommendations may be controversial, such as their choices of meDMTs and HETs, as may be their criteria for assessing high and low risk individuals. Nevertheless, their clear framework of disease and risk assessment, their well-defined treatment options, and their consideration of treatment costs should allow a more uniform, safer and less expensive approach to the management of persons with MS, especially if care is provided by providers not specializing in the management of persons with MS.

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