A Targeted Literature Search and Phenomenological Review of Perspectives of People with Multiple Sclerosis and Healthcare Professionals of the Immunology of Disease-Modifying Therapies

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.

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].

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 [15‐17]. 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.

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:

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.

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.

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).

Of the 40 journal articles and conference abstracts in the analysis, 5 were review articles [19‐23] (including 2 systematic reviews [22, 23]) and 6 were of a qualitative nature, primarily ethnographic and phenomenological studies [24‐29]. 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, 30‐41]. 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, 27‐29, 42‐47]. 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.

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)