Navigating Treatment Decision-Making in Multiple Sclerosis

Prabhu, MD, MRC,Aparna;Khurana, MD,Shikhar ;

Publication

Article

March 24, 2024

NeurologyLive

Spring 2024

Volume7

Issue 1

Navigating Treatment Decision-Making in Multiple Sclerosis

Author(s):

Aparna M. Prabhu, MD, MRCP,Shikhar Khurana, MD

In a paradigm with many options, once multiple sclerosis is confirmed as a patient’s diagnosis, physicians are left with 1 question: What do we choose for long-term treatment?

Aparna M. Prabhu, MD, MRCP

Shikhar Khurana, MD

ONCE A DIAGNOSIS OF multiple sclerosis (MS) is made, it is imperative to consider treatment as soon as possible. On average, a patient with MS has a flare approximately twice a year.¹

The management of MS requires a multipronged and multispecialty approach. A typical team caring for a patient with MS would include the neurologist; neuro-ophthalmologist; other specialists, including a rheumatologist, urologist, and psychiatrist; and a sleep physician. Additionally, the importance of rehabilitation in patients with MS is well established. As such, physical therapists, occupational therapists, pain management teams, physiatrists, and speech therapists would also play a key role in patient care. It is expected that the neurologist orchestrates the patient’s visits to the various specialists and consolidates their input in the care of the patient.

Although disease-modifying therapies (DMTs) are the mainstay of treatment, it is equally important to ensure that the quality of the patient’s life is maintained by optimizing their overall health and offering lifestyle choices and modifications, as well as providing symptomatic treatment for the myriad symptoms that patients with MS may present with. There have been several studies reporting the prevalence of complementary and alternative medicine use by patients with MS, and the range of prevalence is quite broad, at 33% to 70%. This could be in the form of using cannabis for spasticity or yoga and tai chi for muscle relaxation.²

Goals of Treatment With DMTs

No evidence of disease activity (NEDA) status is a goal emerging in the treatment of MS. It aims to treat people with relapsing-remitting MS with DMTs to achieve the following components:

No relapses (measured as annualized relapse rate)
No increase in disability (as measured by the Expanded Disability Status Scale)
No new T2 or active (gadolinium-enhancing T1) lesions on MRI scans

This combination of criteria is sometimes referred to as NEDA-3. However, some studies use NEDA-4, which includes an additional measure: brain shrinkage, or atrophy. In other words, NEDA-4 considers all 3 components of NEDA-3, plus brain volume loss.³

For those with progressive MS, the goal of no evidence of progression or active disease is considered more appropriate than NEDA. In progressive disease, the goal focuses on slowing or preventing disability.

Approved DMTs in MS

The landscape of immunotherapies in the management of MS is ever-changing. As of March 2023, 24 different DMTs had been approved for MS treatment, including injectable, oral, and infused medications, with newer options in the pipeline.⁴ It is an exciting time in the field of MS as we head toward precision medicine.

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Of note, none of the DMTs are approved by the FDA for women who are pregnant, plan to become pregnant, or who are breastfeeding. It is important for women to discuss their plans for pregnancy with their health care provider so they can decide together the best and safest treatment plan.⁴ The 2 prevailing strategies in practice for the treatment of relapsing MS are an escalation approach and an early high-efficacy or intensive approach (FIGURE).

Expert opinion favors the use of high-efficacy treatment for aggressive active disease, though some varying opinions exist. There are 2 ongoing trials—TREAT-MS (NCT03500328) and DELIVER-MS (NCT03535298)—which hope to answer this question specifically, with both trials expected to conclude as early as 2025.⁵

The high number of available DMTs fall into categories of low-, medium-, and high-efficacy treatments (TABLE⁶), though there is no algorithmic or biomarker guided approach to starting a specific disease-modifying agent in a patient newly diagnosed with MS.

If the patient has good prognostic indicators—such as being female or young; having sensory symptoms or optic neuritis, good recovery and/or fewer relapses, or disease activity that spares the brainstem and/or spinal cord—the approach would be to start on 1 of the 3 oral options: teriflunomide (Aubagio; Sanofi), sphingosine receptor blockers, or the fumarate class of medications.

On the other hand, if the patient has poor prognostic factors— such as being male or older; having motor and cerebellar symptoms, frequent relapses, brainstem and/or spinal cord disease, poor recovery between relapses, or significant disability—the approach would be to start on 1 of the monoclonal antibodies: natalizumab (Tysabri; Biogen Inc), if the patient is JC virus negative; ocrelizumab (Ocrevus; Genentech), ofatumumab (Kesimpta; Novartis), or alemtuzumab (Lemtrada; Sanofi).

However, cladribine (Mavenclad; EMD Serono) and the sphingosine receptor blockers would be a good choice for either group of patients. Typically, low-efficacy medications are reserved for patients with very mild disease.

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The decision of when to switch medication for lack of efficacy is informed by the treatment target (see NEDA above). Clinical relapse or progression despite adherence would be an indicator to switch treatment, and adverse effects related to the current treatment would be another indicator. MRI provides a high-sensitivity assessment of DMT effectiveness and should be done at a minimum yearly basis to monitor response to DMT in a patient with relapsing MS.⁵

Ongoing Research and Investigative Treatments

Autologous hematopoietic stem cell transplantation (aHSCT) has been investigated for use in treatment-refractory relapsing MS since the 1990s. There are multiple trials that show promise for the use of aHSCT in this population; however, we need more data regarding the safety of this option as a mainstream treatment modality.⁷ The theoretical basis of HSCT for relapsing MS is that it diminishes pathogenic clones of autoreactive lymphocytes, thereby regenerating the tolerance of the immune system to CD34+ hematopoietic stem cells.⁷

Bruton tyrosine kinase (BTK) inhibitor regimens also remain under investigation regarding MS treatment, including the use of masitinib (primary progressive MS; phase 2b/3); fenebrutinib and tolebrutinib (relapsing MS; phase 2b); and evobrutinib, remibrutinib, and orelabrutinib. The putative benefit of BTK inhibitors over traditional CD20 depletion is that BTK inhibition blocks an enzyme required for B-cell maturation, thereby more selectively removing autoreactive B cells while sparing more tolerant B cells vs CD20 depletion, which broadly diminishes B cell reserves. Research into remyelination also is ongoing and presents potential opportunities for the future.