Patient-Centered Disease-Modifying Therapy Selection for Multiple Sclerosis: Addressing Routes of Administration

The wide range of DMTs now available to treat multiple sclerosis (MS) has been game changing for patients and clinicians alike, but as with anything, more choices generate new issues. Each therapy affects individual patients differently, and the decisions patients have to make are more complex. Not only can patients switch medications, but they need to consider different modes of administration.¹
 
Anne H. Cross, MD, is a professor of neurology and the Manny and Rosalyn Rosenthal Dr John Trotter MS Chair in Neuroimmunology at Washington University in St. Louis, Missouri. She has been an MS clinician for 33 years. In this article, Dr Cross describes how she guides patients through challenging treatment selection decisions.

Given the wide array of available treatments for MS, what administration issues appear to have the greatest impact on individual patients and on choosing DMTs?

In over 33 years of taking care of patients with MS, my impression is that factors specific to the patient, as well as their personality and motivation, are most important to adherence to therapy with any administration mode. Some people are highly motivated to take whatever is recommended to them by their physician and to take it as perfectly as possible. They are willing to do whatever is needed to have the best treatment, and they report never missing a dose.
 
Some people are very sensitive to side effects, so they delay or skip doses. Pain and discomfort, including nausea, are probably the 2 things that bother patients most. The side-effects-sensitive patient may become anxious about taking the medication due to the side effects. If it is administered by self-injection, this can sometimes be overcome by having a family member or friend do the injections. However, now that we have a wide variety of disease-modifying MS medications administered in different ways, it is often best to discontinue a drug to which a patient has trouble adhering.
 
Some people do not recognize the importance of adherence to therapy, and it is our job to educate patients about this. A systematic review of studies on adherence to MS medications found several that suggested that better adherence to medication was associated with being better informed about the disease itself and the treatment. Several studies found men to have higher rates of adherence to therapy than women. Older people had better adherence than younger people with MS. The age cutoffs varied across studies, but generally, those aged 45 years and older adhered better. Interestingly, people with more education had lower adherence in 2 studies that were reviewed.¹
 
Cognitive impairment is associated with reduced adherence to DMT for MS. Forgetting to take a medication can be a problem. Close family members or friends can be enlisted to help with adherence. Patients may have physical barriers to taking certain treatments that require dexterity, such as some self-injections. Depression is not uncommon in people with a diagnosis of a chronic, incurable neurological illness and should be treated appropriately.¹ Others may refuse to accept that they have MS, and more than 1 relapse may be needed to convince them of their diagnosis and that it should be treated.
 
It is helpful to understand the person and their goals and fears before choosing a DMT, and that usually requires more than 1 encounter. Several visits a few weeks apart at the beginning can be useful for understanding the individual person with MS, as well as for educational purposes. It can be enlightening to ask patients, “How many doses of medication are you missing?” When the question is phrased this way, the patient will understand that we know people are going to miss some injections or doses of medication, but we do not want it to be too many. One reason I like infusions is that they are delivered by someone else in a controlled environment. Staff at the infusion center will let us know if the patient is experiencing side effects or does not show up for their infusion. For patients who have trouble remembering to take a scheduled medication, going to a specific site for infusion can keep them on track.

How do you approach talking to patients about the risks and benefits of DMTs?

Typically, I will discuss with the patient my assessment of their disease prognosis and severity. My assessment is not always correct, and I make sure to tell them that. Over the past few decades, our field has learned about several negative prognostic factors, such as multifocal onset, lack of full recovery from prior attacks, short time between first and second relapse, multiple lesions in the spinal cord, and multiple cerebrospinal fluid-specific oligoclonal bands. All these prognostic factors are at the group level, and there are exceptions and nuances. Biofluid biomarkers, such as glial fibrillary acidic protein and neurofilament light chain, are on the horizon as potential prognostic indicators.²
 
For people who have several of these bad prognosis indicators, recommending a more highly effective DMT is prudent, even if that medication may carry more risks. Conveying hopefulness when delivering this type of message is important. The discussion can be focused on more highly effective DMTs. We can have a discussion about whether the patient prefers to self-inject, such as with ofatumumab monthly subcutaneous injections, or to use an intravenous infused medication that requires them to go to an infusion facility. This is helpful in prescribing a medication to which the patient is likely to adhere and involves the patient in therapy choice.

The initial choices patients make have a strong impact on treatment adherence and therefore the outcome. How do you manage the theories of treatment in conjunction with the real-world experiences of patients on these therapies to maintain optimal adherence?

When MS patients admit to missing more than 20% of their DMT doses, I consider that insufficient treatment. Even a lesser degree of nonadherence may impact patient outcomes. With some of the DMTs, stopping them suddenly puts the patient at risk for worsened MS activity. This can get tricky if insurance is abruptly lost. The risk of rebound probably requires reinforcement during subsequent visits. Patients should be made aware that rebound can happen when some DMTs are stopped so they do not stop their medication without a discussion about what DMT they will go on next.
 
When discussing initial therapy, I tend to first group medication in “bins” based on mechanism of action. Once a particular bin is chosen—such as a beta-interferon, a fumarate, a sphingosine 1-phosphate receptor modulator, or a B cell depleting agent—then we can get into specifics about the medications in those bins.

High-efficacy DMTs are increasingly being advocated as first-line therapies for relapsing/remitting MS. What is your experience with patient preferences in this context, and how well do they understand the consequences of different choices?

Most patients will not have a good grasp of MS when they are initially diagnosed with it. Additionally, we cannot predict how this disease may affect individual people in the future. Our role as clinicians includes educating our patients on the risks of this disease itself, in terms of later disability, and on the potential risks of the medications we prescribe. There is no algorithm that can say with certainty the prognosis for an individual person with MS. Using the imprecise methods we have now, we can attempt to prognosticate whether an individual’s disease will be aggressive and lead to significant neurological impairment or they might be one of the fortunate people with more benign MS.
 
Occasionally, a patient will want to decide what DMT to undergo, and it is very appropriate for each patient to have input into what therapies are chosen. However, we as clinicians have the responsibility to guide them. We have the educational background and expertise in their particular disease to help them make the best choice.
 
Discussing the possibility of pregnancy is important because DMT choices are limited if pregnancy might occur in the near future.³

How do you assess individual patients’ satisfaction with treatment and the real success of the chosen modality over the course of therapy? How often is this discussed, and what patient issues trigger therapy changes?

The question of patient satisfaction can be answered by asking the patient directly. Judging the success of the chosen DMT is based on 3 factors: effectiveness, tolerability, and safety. After giving a DMT time to become effective, is there ongoing disease activity? Nowadays, we have medications that will halt relapses and disease activity in most patients with relapsing MS. So if patients are having true relapses or they are having new lesions or gadolinium-enhancing lesions on a magnetic resonance imaging (MRI) despite taking the medication correctly, the treatment effect is suboptimal and the drug is “failing” in their case. Serial neurological examinations and MRIs are recommended to be done approximately yearly (every 6 months to every 2 years) to look for new lesions; this is important because these tests will reveal whether MS activity continues despite treatment.⁴
 
Patients can be instructed to call the neurology office with any new neurological symptoms, and they will need education on what these symptoms might be. If the DMT is not performing optimally, then a discussion with the patient about what other DMT options are available is needed. Given that we have several highly effective DMTs now, having this discussion soon is important. Other issues that may trigger this discussion include intolerable side effects or health risks due to the medication. A different agent might be needed for a woman planning a pregnancy. Repeated infections in a person who is taking an immunosuppressive DMT, highly abnormal laboratory values that are likely to have been caused by the DMT, or a positive John Cunningham virus antibody with a high index in a person who is on natalizumab would trigger the need for a change.
 
A study by Hoffman and colleagues examined the balance between treatment risks and benefits as well as changes over the course of therapy impacting adherence. The results indicate that real-world patient preferences often do not factor into the initial selection of a DMT, which is often chosen by the provider based on safety profiles rather than the stated therapeutic preferences of the person with MS.⁵
 
Specific preferences of patients need to be considered. Clinicians may not always initiate therapy using a “highly effective therapy” if that treatment also carries significant health risks. We have been taught to follow the ethical principle primum non nocere, which means “first, do no harm.” However, this adage does not mean that clinicians should not use treatments with risks if the benefits justify those risks.
 
This Q&A was edited for clarity and length.

Disclosures

Anne H. Cross, MD, reported affiliations with Biogen, Inc; Bristol-Myers Squibb Company; Novartis Pharmaceuticals Corporation; Genentech, Inc/Roche Holding AG; EMD Serono, Inc; Octave Bioscience, Inc; and Horizon Therapeutics, plc.

References

1. Washington F, Langdon D. Factors affecting adherence to disease-modifying therapies in multiple sclerosis: systematic review. J Neurol. 2022;269:1861-1872. doi:10.1007/s00415-021-10850-w
 
2. Meier S, Willemse EAJ, Schaedelin S, et al. Serum glial fibrillary acidic protein compared with neurofilament light chain as a biomarker for disease progression in multiple sclerosis. JAMA Neurol. 2023;80(3):287-297. doi:10.1001/jamaneurol.2022.5250
 
3. Krysko KM, Dobson R, Alroughani R, et al. Family planning considerations in people with multiple sclerosis. Lancet Neurol. 2023;22(4):350-366. doi:10.1016/S1474-4422(22)00426-4
 
4. Traboulsee A, Simon JH, Stone L, et al. Revised recommendations of the consortium of MS centers task force for a standardized MRI protocol and clinical guidelines for the diagnosis and follow-up of multiple sclerosis. Am J Neuroradiol. 2016;37(3):394-401. doi:10.3174/ajnr.A4539
 
5. Hoffmann O, Paul F, Haase R, Kern R, Ziemssen T. Preferences, adherence, and satisfaction: three years of treatment experiences of people with multiple sclerosis. 2024;18:455-466. doi:10.2147/PPA.S452849