FormalPara Key Summary Points

Why carry out this study?

The mechanisms of action of disease-modifying therapies (DMTs) for multiple sclerosis (MS) are complex and involve an interplay of T cells, B cells, and other immune system components.

Informed, shared decision-making empowers people with MS (PwMS) and results in improved care, but many PwMS may not be familiar with or fully understand the immunological concepts involved, and healthcare professionals (HCPs) may not be able to communicate the concepts clearly.

What was learned from the study?

This study involved a targeted literature search to establish PwMS preferences for safety and efficacy of DMTs through routes that optimize independence, and to identify unmet needs for improved communication between HCPs and PwMS.

A qualitative survey of the patient authors of this work confirmed these findings and provided phenomenological insights into the decision-making process.

This review involving patient and care-partner authors further seeks to counter the identified unmet need for better communication by providing plain language explanations and figures of immune mechanisms in MS to serve as information tools for HCPs to use when communicating and discussing immune concepts with patients.

Interactive Infographic

This article contains an interactive infographic of the immune system in MS. To view it, click here: https://sn.pub/BOTxix.

Introduction

Multiple sclerosis (MS) is a chronic, progressive, immune-mediated disease characterized by demyelination of the central nervous system leading to neurological and physical disability [1, 2]. It is estimated that MS affects over 2.8 million individuals worldwide [3], and the prevalence in the USA has been estimated to be as high as 1 million people [4]. Owing to the complexity of the disease, theories of MS immunopathogenesis have evolved over the years, with current models focusing on the interplay of T and B cells, evidenced by the overlap of effects on these cell subsets by disease-modifying therapies (DMTs) [5].

Many people with MS (PwMS) may not be familiar or comfortable with MS terminology, including immunology and drug mode/mechanism of action (MoA) terms [6]. However, given that healthcare professionals (HCPs) and PwMS consider many factors when selecting a DMT, such as efficacy, safety, administration route, and frequency, broader comprehension of MS immunology and terminology would be useful. A better understanding of potential treatment effects may lead to more informed decision-making when choosing DMTs. However, the importance and relevance to PwMS of comprehending these concepts in informing choices when selecting new DMTs is not currently known. Moreover, PwMS’ understanding of how DMTs can affect B and T cells, and interpretations of risk and administration preferences for therapies, may have been influenced by the coronavirus disease 2019 (COVID-19) pandemic. While safety and efficacy may be expected to take precedence over MoA knowledge in PwMS’ considerations of DMTs, understanding treatment MoAs can meaningfully inform safety and efficacy, and there is a clear need for such information to be more clearly and consistently accessible, in terms of both content and methods of communication. These concepts were initially identified and explored in a poster presented at the MS Virtual 8th Joint ACTRIMS-ECTRIMS Meeting 2020 [7].

The Immune System in MS

While MS pathogenesis is highly complex and not fully elucidated, it is understood to be mediated in part by the interplay and balance of B and T cells [5]. In MS, multiple immunological and inflammatory processes, including axonal damage and demyelination, gliosis, cortical neurodegeneration, and neuronal loss, result in atrophic lesions in the brain [8, 9]. These processes are largely driven by: (1) effector B cells and B-cell lineage plasmablasts and plasma cells generating autoreactive oligoclonal antibodies, (2) circulatory cytotoxic T cells that have migrated across the blood–brain barrier, and (3) complement elements and other innate components of the immune system such as microglia and inflammatory mediators such as cytokines [8, 9]. Furthermore, there is an imbalance in the regulatory T and B cells that usually keep these inflammatory and cytotoxic processes in check and maintain immunological homeostasis, resulting in unregulated immune-mediated tissue damage (Fig. 1) [10]. See “Box 1” for a lay language explanation of MS immunology.

Fig. 1
figure 1

The balance of the adaptive immune system and MS. a The resting immune system. On one side, inflammatory and reactive mechanisms limit infections and respond to foreign antigen. On the other side, regulatory mechanisms keep the adaptive response in check and maintain a homeostatic balance. b The immune system during an infection. The infection has already shifted the balance towards tolerance, so inflammatory and reactive mechanisms are upregulated to fight the infection and restore homeostasis. Regulatory mechanisms are downregulated. c The immune system in MS. The balance is shifted towards autoimmunity and autoreactivity, but the regulatory homeostatic mechanisms are not sufficient to curb the immune responses. Autoreactive lymphocytes migrate into the central nervous system and through a number of pathogenic mechanisms cause widespread demyelination, gliosis, and neurodegeneration, forming lesions of atrophic brain tissue. MS multiple sclerosis

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Disease-Modifying Therapies and Their Mechanisms of Action

DMTs are immunomodulatory therapies that can change or alter the MS disease course by reducing the number of relapses, reducing the appearance of new lesions on magnetic resonance imaging, and slowing progression and atrophy [11, 12]. Recent evidence has shown that there is significant interplay and an overlap of the effects of DMTs between lymphocyte subsets [5, 13]. The relationship between B and T cells is highly complex, and introducing immune modulation into this system can have clear impacts on the balance of these cell populations. At the time of publication, there are 22 branded or generic variations of DMTs approved by the US food and Drug Administration for the treatment of relapsing MS, which can be summarized into five overall drug categories based on their immunomodulatory effects (Table 1) [14].

Table 1 Categories of FDA-approved disease-modifying therapies for MS [14]
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The majority of DMTs have direct impacts on most lymphocytes, but some can target specific populations. The small-molecule modulators of the sphingosine-1-phosphate receptor prevent egression of autoreactive T cells from the lymph nodes and downregulate inflammatory mechanisms. However, non-lymphatically sequestered cells such as circulatory effector B cells are known to be unaffected by this MoA [15,16,17]. Anti-α4-integrin monoclonal antibodies prevent endothelial migration of lymphocytes across the blood–brain barrier into the central nervous system. Anti-CD52 monoclonal and DNA synthesis and repair inhibitors are immunosuppressive and immunoablative agents that mediate lymphocyte depletion of both B and T cells [15]. However, there are also B-cell-specific depletion therapies, anti-CD20 monoclonal antibodies, that act mostly on B lineage cells; Bruton’s tyrosine kinase inhibitors are also being investigated as potential B-cell-specific therapies [18]. Finally, fumarate therapies, interferon therapies, and glatiramer acetate all act to suppress and mitigate inflammatory processes via nuclear factor erythroid 2-related factor 2 pathway downregulation, interferon receptor activation, and myelin basic protein mimicry, respectively (Fig. 2). See “Box 2” for a lay language explanation of DMT MoAs.

Fig. 2
figure 2

The effect of DMTs on the immune system in MS. (1) S1P receptor modulators prevent autoreactive lymphocytes from egressing from the lymph nodes via S1P receptor downregulation. (2) Endothelial migration of autoreactive lymphocytes across the blood–brain barrier is blocked by anti-α4-integrin activity. (3) Immunosuppression and lymphocyte cell death to varying degrees are driven via inhibition of DNA synthesis and repair mechanisms and anti-CD52 activity. (4) B-cell depletion and death via B-cell-specific anti-CD20 activity. (5) Glatiramer acetate mimics myelin basic protein to redirect inflammatory responses; fumarate therapies downregulate the Nrf2 pathway to slow inflammation. (6) Interferon therapies mimic interferons to upregulate inherent immunosuppressive mechanisms of the regulatory immune system. CD cluster of differentiation, DMT disease-modifying therapy, Nrf2 nuclear factor erythroid 2-related factor 2, S1P sphingosine-1-phosphate

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Review Aim

This review aims to assess and to evaluate the level of PwMS involvement in MS treatment selection, the importance for PwMS to understand MoA when discussing DMTs with HCPs, and to gain insights from PwMS and physicians to provide a wider context for treatment selection conversations. This review explores the existing literature and presents the findings of a survey in PwMS to establish existing preferences for DMT selection and shared decision-making processes, and to define the unmet need for better PwMS–HCP communications. By exploring the factors most important to PwMS, care partners and physicians when considering potential DMTs, this review will help to educate HCPs on the benefits of shared decision-making and how to have meaningful MoA conversations with PwMS. Ultimately, the goal is to support improved shared decision-making regarding DMT selection between PwMS and their HCPs.

Methods

Targeted Literature Review

The targeted literature search was performed in June 2020 using Ovid in the Embase and MEDLINE databases of all available English-language articles and conference abstracts with no time limit using the following search terms:

  1. 1.

    (Patient or stakeholder).ti.

  2. 2.

    (Perspective$ or insight$ or understanding or knowledge or engag$ or empower$ or preference$ or communicat$).ti.

  3. 3.

    Multiple sclerosis.ti.

  4. 4.

    (“disease modifying therap$” or “disease modifying treatment”).af.

  5. 5.

    (“mechanism of action” or “mode of action”).af.

  6. 6.

    1 and 2 and 3.

  7. 7.

    1 and 2 and 3 and 4.

  8. 8.

    1 and 2 and 3 and 5.

Further, manual searches were performed using different combinations of the above search terms on PubMed. Titles were initially screened manually for duplication and direct relevance to the current objective. Reference lists were also screened for any further titles that were of relevance. The remaining resources were then categorized according to their methods (qualitative, quantitative, or review) and analyzed in full. See “Box 3” for a lay language explanation of the methods.

Survey and Correspondence Insights

The specific methods of data collection for the questionnaire have been presented elsewhere [7]. In brief, a qualitative questionnaire was designed by two authors (A.R. and J.L.W.) in December 2018 based on preliminary discussions with the patient authors. This was designed to explore factors most important to PwMS when considering potential DMTs following a phenomenological PwMS narrative approach. This included PwMS’ understanding of the immunological processes of MS and the MoAs of MS treatments, and preferences regarding route of administration and provision of MS clinical information. The questionnaire was distributed via email to three PwMS (J.B., D.C., and T.S.) and one care partner (J.C.) based on their advocacy expertise and involvement in the patient-authored literature, all of whom are authors of this work. General insights were gathered from the HCP authors (two neurologists [J.G. and A.Z.O.], a pediatric neurologist [M.L.S.], and a physician assistant [J.K.]) via personal correspondence, based on their professional expertise and established relationships. Ethics committee approval was not required for this survey, which was performed in accordance with the Helsinki Declaration of 1964 and its later amendments. All survey respondents who are also authors of this publication provided informed consent to participate in the survey and for their responses to be included in this publication. This was a noninterventional qualitative survey conducted by Novartis in the USA to assess PwMS and HCP opinion. The research followed General Data Protection Regulation guidance. Survey respondents did not receive any incentive payment for completion of the survey, and all participated as authors in the development of this manuscript, in compliance with the International Committee of Medical Journal Editors authorship requirements and Good Publication Practice.

Results

Targeted Literature Review

The search string [(patient or stakeholder).ti.; (perspective$ or insight$ or understanding or knowledge or engag$ or empower$ or preference$ or communicat$).ti.; multiple sclerosis.ti. AND (“disease modifying therap$” or “disease modifying treatment”).af.] yielded 39 results on Ovid. Following screening for relevance to the current objective and the removal of duplicates, this was then narrowed down to 20 articles for review. The search string [(patient or stakeholder).ti.; (perspective$ or insight$ or understanding or knowledge or engag$ or empower$ or preference$ or communicat$).ti.; multiple sclerosis.ti. AND (“mechanism of action” or “mode of action”).af.] did not yield any results, confirming the unmet need for assessment of PwMS’ understanding of MoA. Subsequently, manual searching of the literature on PubMed using the same keywords yielded an additional 6 articles, and full-text review of all search results and the reference lists identified 14 more articles with relevance to the current objective. In all, 40 journal articles and conference abstracts are included in the current review (Fig. 3; Table 2).

Fig. 3
figure 3

Flow diagram of the results of the targeted literature search. Searches performed in June 2020

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Table 2 Results from the targeted and manual literature searches
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Of the 40 journal articles and conference abstracts in the analysis, 5 were review articles [19,20,21,22,23] (including 2 systematic reviews [22, 23]) and 6 were of a qualitative nature, primarily ethnographic and phenomenological studies [24,25,26,27,28,29]. The remaining 29 publications were quantitative surveys or discrete-choice experiments and conjoint analyses—common statistical methods for ranking attributes within preferences [30–58].

Independence and convenience of administration are recognized as critical factors in selecting DMTs to initiate therapy or to switch therapy; accordingly, 12 of the quantitative items and 3 qualitative items found a preference or perceived suitability for oral administration, ranging from 31% to 93% of surveyed PwMS cohorts preferring this method [24, 27, 28, 30,31,32,33,34,35,36,37,38,39,40,41]. Overall, 6 quantitative and 5 qualitative items explored the role of PwMS–HCP communications in shared decision-making and patient satisfaction with the level of engagement [24, 25, 27,28,29, 42,43,44,45,46,47]. In the phenomenological studies, the majority of PwMS were actively involved in decision-making, considered their neurologist a useful figure in their MS treatment path, and were the key drivers of DMT decisions. Across the analyses, technology and education were identified as principal factors for optimizing communication within health services and improving overall patient satisfaction. It is widely acknowledged in the literature and in the medical community that patient satisfaction and understanding can lead to improved treatment adherence and better health outcomes.

Patient Survey and HCP Insights

In addition to the literature review, a preliminary qualitative survey was undertaken to obtain perspectives and insights from PwMS and HCPs on the importance of understanding the MoAs of DMTs. The results from the survey may be helpful in informing and designing future studies that will assess these needs more widely. The full responses to the open-response questions are presented in the Supplementary Material. Overall, the PwMS and care-partner respondents were largely in agreement with the current literature, reporting that safety and efficacy are equally the most important attributes to consider when making DMT decisions, and that routes and modes of administration that offer independence are preferable to those that require HCP oversight.

“A large factor in selecting a medication is how well will it treat my MS and prevent further progression. Next, I want to know the side effects of the medication and how will it affect my body overall. I like to know what are the large concerns [when] taking a medication and short term [concerns]. Another priority is the method in which you deliver the medication. For example, a pill, infusion, or shot. Finally, how often the medication is required to take. For example, daily, weekly, monthly, etc.” (Tim Sabutis)

“If [efficacy] and side effects are all equal then I suppose I wouldn’t care too much about how it works. I would like to know what it would be doing to my body, but in the end, if it’s all equally safe and effective, how it works would not matter much.” (Daisy Clemmons)

“I remember before there was a pill form of treatment for MS and the MS community was begging to know when it would be available. The answer was always “in 5 years”. I don’t know anyone who would choose an injection or infusion over a pill. It seems like there is less risk involved during administration to only swallow a pill. I’d rather be at home and take the pill myself.” (Jeri Burtchell)

With regard to immunological terms and drug MoAs, PwMS and care-partner respondents felt they had a better understanding of overall processes (e.g., of the overarching role of the immune system in MS) than they did of specific mechanisms (such as the interplay of T cells and B cells and their role in MS pathophysiology). It was recognized that MoA knowledge among the patient respondents is currently lacking but represents an area of interest in which to build communication and develop educational material.

“I feel like I have a strong grasp of demyelination vs inflammation in MS. I have done a lot of research on MS and the disease-modifying drugs. The role of B cells vs T cells is something I have not done much research on, however, but am very eager to learn more as B cells become more of a target in emerging therapies. I have some idea of what biologics are and how they work but not a solid understanding…I’ve always been curious about the mechanism of action with any drug I take, whether it’s for a migraine or for MS. I feel like knowing how drugs work allows me to make better informed choices when it comes to selecting treatments. Understanding the MoA can also shed more light on why certain side effects may be likely to occur. Knowledge is power and when you have a chronic illness like MS it’s important to learn all you can about every aspect of the disease and how it’s treated… While I feel like I know a lot about MS and about the various treatment options, I know little about their MoAs and what makes B cells or T cells the best targets for treatments. I would love to learn more, especially when it comes to targeted therapies and knowing what works best for an individual based on their type of MS and unique set of symptoms or circumstances.” (Jeri Burtchell)

Patient and HCP respondents all reported that face-to-face discussions, supplemented with visual aids such as animations, were preferable to noninteractive materials such as leaflets and websites; one patient further identified the environmental impacts of paper distribution as a negative factor. Crucially, the survey and subsequent correspondence identified the necessity for information delivery to be tailored to the needs of individuals.

“Having information about how the treatment works explained to me by a medical professional using patient-friendly language would be the best option. This allows me to ask questions and get immediate clarification. Websites and videos can also provide FAQ-type answers and be a resource that is readily accessible 24/7 when I may not be able to contact my doctor. Everyone has their own learning style and others may feel having a leaflet is important. I am more visual and would like to have an explainer video that walks me through how a treatment works. I am also trying to become more environmentally conscious and would probably not take a leaflet if I can avoid it. I prefer digital over paper when possible.” (Jeri Burtchell)

“I think it is important to use the mode of learning that is effective for the patient. For me, watching and seeing a video is the most effective strategy for me to learn. It is important for the care professional to meet the client where they best learn to communicate about the disease-modifying treatments.” (Tim Sabutis)

“I would prefer a medical professional in case I have questions. They would be able to give an explanation tailored for my needs when trying to understand.” (Daisy Clemmons)

In addition, HCP respondents identified the need for increased face-to-face time in the clinic to allow for such conversations to take place.

“Increased access to technology, credit for time spent on phone, and more face-to-face time in clinic is always needed.” (Michael L Sweeney)

“Providers need more time for education.” (Jennifer Graves)

“[It is important to spend] time on discussing a personalized approach in therapy selection and shared decision [making] with [the] patient.” (Ahmed Z. Obeidat)

Discussion

The findings from the targeted literature search and qualitative survey employed in this review were largely in agreement, and were consistent with the literature regarding PwMS preferences; the findings from both methods highlight a knowledge gap in the importance of understanding MoA immunology by PwMS when making DMT decisions, which this review aims to address in part. The perspectives from the HCP and PwMS authors were also aligned, demonstrating a need for more resources for communication of such concepts, personalized education, and a desire from PwMS for improved health literacy.

Moreover, the findings from both of the methods confirmed expectations of safety and efficacy taking priority in determining factors of DMT decision-making, followed by methods of administration, with the majority of PwMS reporting a preference for methods that allow for autonomy and independence (e.g., oral administration or treatment that can be administered at home).

This desire for more independence in administration represents a wider shift in philosophies of medical practice, favoring patient empowerment and shared decision-making over the more traditional, paternalistic approaches to delivering healthcare. Shared decision-making is a critical aspect of enabling patients to make fully informed healthcare choices [59]. This cooperative approach is particularly important and advantageous for preference-sensitive conditions with a wide range of treatment options that vary in their attributes, such as MS [20]. The evidence base for the efficacy of shared decision-making models, patient engagement practices, and health literacy approaches in MS specifically is limited but has been presented in a Cochrane Library systematic review, concluding that information provision in MS leads to improved disease-related knowledge compared with no information provision [60]. In the UK, both the National Health Service and the National Institute for Health and Care Excellence assert that shared decision-making has the potential to lead to improved health outcomes for patients [61, 62]. Regardless, the need for shared decision-making is not solely evidence-based but is also an ethical and moral imperative.

However, successful shared decision-making is dependent both on sufficient health literacy among patients and on satisfactory communication and materials from HCPs. In a recent meeting where multiple stakeholders gathered to identify unmet areas of need in MS care, the Members of the MS in the 21st Century Steering Group highlighted the urgent need for improved patient engagement in MS care and research [29]. Many resources exist to aid the delivery of healthcare centered around shared decision-making, notably the Armstrong 2016 Framework for Shared Decision-Making and Neurology, which presents a stepwise approach to: (1) identify a patient’s values and goals, (2) present evidence as it relates to their values and goals, and (3) arrive at a decision with the patient [63]. Many other educational programs, decision support techniques, health literacy tools, and treatment-specific decision aids have also been developed to enable shared decision-making healthcare, to provide language for effectively communicating MS concepts, and ultimately to empower PwMS to arrive at a fully informed healthcare decision [20, 64].

Furthermore, the COVID-19 pandemic has resulted in significant interruptions to the normal delivery of healthcare across all specialties and has introduced many uncertainties, particularly in the treatment of immunological and autoimmune conditions. Immunomodulatory and immunosuppressive therapies are known to incur risks associated with infectious disease, although the exact interactions of COVID-19 with DMTs for MS are largely unknown. Given the broad repertoire of these therapies, there are significant variations in risk analyses, with many guidelines and opinions largely agreeing that cell-depletion therapies likely present the highest risk [65, 66]. At the same time, the discussion of immunology and immunological terms has become more commonplace as mainstream news sources frequently report on developments in vaccines and antigen and antibody tests; this “infodemic” may in turn influence public interest in understanding immunology and immunological health literacy, and interpretations of risk in other contexts [67, 68]. Evidence of the effects of COVID-19 on DMT selection and risk monitoring in MS is a rapidly evolving knowledge base, and communications with PwMS should reflect this.

“The COVID-19 pandemic forced us to rethink our approach in treating MS patients with DMTs. Our initial concerns are readily obvious: Do the current DMTs used in MS patients cause an increased risk of developing COVID-19? Once infected, do the current DMTs in MS cause patients to have worse outcomes than immunocompetent patients? The short answer is that we don’t know the answers to these questions yet … In the absence of robust data, clinicians are forced to have a similar conversation that we had with patients prior to the COVID-19 pandemic: What are the risks/benefits of starting a DMT or for a patient currently taking a DMT?” (John Kramer)

This review had several limitations owing to its limited scope and qualitative nature. The restricted number of survey respondents allowed for a more in-depth, phenomenological approach to the analysis of the free-text response questions but may have limited applicability to a wider context and was not fit for quantitative analysis. Additionally, performing a targeted literature search enabled the precise unmet need of insufficient patient communications regarding DMT MoAs to be defined; however, the authors acknowledge that these methods are not as robust as a full systematic review.

It is pertinent in this review to recognize and to acknowledge the shifting paradigms in MS theory—in wider understanding both of immunological pathogenesis and of specific immunological MoAs of DMTs—and to ensure that PwMS communications take this into account. For example, MS has historically been considered a demyelinating disease, but recent narratives have shifted towards a whole-brain disease model that considers wider elements of pathogenesis and neurodegeneration [69, 70]. Additionally, it is becoming increasingly clear that even DMTs traditionally thought of as specifically targeting T and/or B cells or other immune components more likely have widespread holistic effects on the immune system [5, 70]. For the sake of transparency and fully informed shared decision-making, it is prudent to acknowledge how the literature has evolved and where gaps remain in our understanding, particularly in individual responses to the therapy and real-world effects.

Conclusions

Effective communication regarding the MoAs of DMTs has the potential to empower PwMS to take the lead in their therapeutic choices with guidance from HCPs in a shared decision-making model. In addition, our preliminary survey, introduced here, could be implemented in larger cohorts to gather further insights and to quantify findings in order to establish more specific areas of unmet need and to develop best practices for communicating immunology to PwMS.