Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system affecting over 2.8 million worldwide, often manifesting in adults aged 20–40, with women affected more than men. Its unpredictable symptoms, like fatigue, impair mobility and quality of life and cognitive dysfunction posing burdens on individuals, families, and healthcare systems (1, 2). It is the most common cause of non-traumatic disability in young and middle-aged adults (3, 4). MS is characterized by neurodegeneration caused by axonal injury, present from the early disease stages (5, 6). Due to the high variability of MS, in which the disease can manifest very differently between individuals and over time in the same patient, clinical and radiological markers may not be specific or sensitive enough to capture the full range of changes in terms of inflammation and neurodegeneration (7). Assessment and quantification of inflammatory activity and neurodegeneration are essential to establish the severity of the disease, the long-term prognosis, the need for treatment, the treatment option and the individual response to the selected treatment, as well as the achievement of therapeutic goals (7, 8).

The neuronal cytoskeleton is composed of actin, microtubules and neurofilaments (9). Neurofilaments are mainly located in myelinated axons, where they help maintain axonal structure and enable high-speed nerve conduction. Extracellular secretion of neurofilaments from the neuronal cytoskeleton has been registered in the context of axonal injury and neurodegeneration. Neurofilaments, once released into the extracellular space, reach the cerebrospinal fluid (CSF) and bloodstream. Light and heavy chains are sufficiently stable to be detected in blood by immunoassay and light chains allow longitudinal blood determination in clinical practice with high sensitivity and by a minimally invasive procedure (9). In this context, the assessment of blood-based neurofilament light chain (blood-based NfL) concentration in MS is becoming a practical tool for predicting clinical outcomes and monitoring subclinical disease activity in response to treatment (9–11). Indeed, elevated levels of blood-based NfL have been related to inflammatory activity, in terms of occurrence and severity of clinical relapses and increased frequency of lesions (12). Additionally, elevated levels of blood-based NfL have been associated with neurodegeneration, in terms of progression of physical and cognitive disability, as well as brain atrophy (5). Besides, assessment of the response to MS treatments could be another application of quantification of blood-based NfL and, in the future, could facilitate treatment choice in high-risk patients as a marker of response to treatment (5, 9, 13–17). Nevertheless, one of the significant challenges hindering the widespread utilization of NfL lies in its non-specific nature. Unlike some biomarkers that exhibit a high degree of specificity to specific pathological processes or diseases, NfL levels can be influenced by various factors beyond MS, including other neurodegenerative conditions, acute neurological insults, and even non-neurological disorders. This lack of specificity poses a critical hurdle in interpreting NfL measurements accurately and underscores the importance of contextualizing its levels within the broader clinical and pathological landscape (18–20).

Other blood and cerebrospinal fluid biomarkers are also being studied as biomarkers in MS (21). Particularly, there is growing interest in a novel blood biomarker known as glial fibrillary acidic protein (GFAP) in the field of neurological diseases (22). Its potential complementary role alongside blood-based NfL could significantly enhance prognostication and the development of disease management strategies for MS (23).

Multi-Criteria Decision Analysis (MCDA) enables determination of the value contribution of a health technology from the perspective of all stakeholders (clinicians, hospital pharmacists, patients, evaluators/payers, hospital directors and regional healthcare directors), stimulating structured discussions among all of them through an explicit set of quantitative and qualitative criteria (24, 25). This systematic, structured, objective, and transparent process allows for a more complete analysis of the overall value. It also provides arguments for decision-making, considering all criteria relevant in health care evaluation and decision-making, beyond the traditional assessments based on efficacy, safety, and cost (26).

The objective of this study was to determine the value contribution of blood-based NfL as a biomarker in MS in Spain using the MCDA methodology.

The value contribution of blood-based NfL as a biomarker in MS was assessed through reflective MCDA by a multidisciplinary panel of stakeholders involved in the management of MS and decision-making in Spain.

MS is perceived as a severe disease with high morbidity and high impact on life expectancy due to disease activity and neurodegeneration. Patients experience a significant impairment in their quality of life because of the disability associated with the disease (3, 39). MS is also considered to have high prevalence, affecting over 2.8 million worldwide (1, 2, 40, 41). Unmet needs have been identified in the determination of disease activity, measurement of neurodegeneration, and response to treatment of patients with MS at an early stage. Traditionally, clinical and radiological variables have been used to assess these outcomes, but they usually reflect an already established neurological damage. Thus, a biomarker capable of determining both inflammatory activity and neurodegeneration and identifying patients at risk of disease progression at an early stage is urgently required (9, 10). It is also essential to promptly initiate optimal treatment, continuous monitoring of therapeutic response, anticipation of treatment decisions, and achieve better therapeutic individualization. The final aim is to improve the quality of life for both patients and caregivers (5, 9, 13–16, 42).

The results of this study suggest that quantification of blood-based NfL could be used to determine disease activity, complementing clinical and radiological information. In addition, measurement of blood-based NfL may be used to establish inflammation-associated neurodegeneration, identifying patients who are entering the neurodegenerative stages of the disease. It has also been considered that blood-based NfL, as a biomarker of neuronal damage, could provide value in determining treatment response at an earlier stage than clinical or radiological variables. The reason is that blood-based NfL reflect neuronal inflammation at a deeper level than MRI or clinical manifestations. Its integration into clinical practice could enhance the process of selecting appropriate treatments, evaluating treatment responses, and ensuring ongoing monitoring of therapeutic efficacy. This would involve identifying patients who require treatment due to worsening disease progression, patients who can safely discontinue treatment due to disease improvement, or patients at risk of treatment failure or severe adverse reactions, thereby indicating the need for a change in treatment (9, 16, 43). Blood-based NfL is not specific to MS, which implies that it is not a diagnostic marker for MS (10). Nevertheless, measuring blood-based NfL levels could still have value in providing complementary data to enhance the sensitivity and specificity of MS diagnosis. This is especially relevant in patients with clinically isolated syndrome or in the early stages of the disease that do not yet meet established diagnostic criteria (5, 9, 13, 14, 16, 17, 42). Participants consider blood-based NfL as a highly secure biomarker. To quantify blood-based NfL, a patient’s blood sample is required, obtained through blood extraction (5). This test is routinely and regularly performed, considered low-risk and safe, with potential adverse effects being rare and generally mild and tolerable, which contributes to a good safety profile of the intervention. In fact, the risks associated with blood extraction are perceived to be negligible. Given that patients with MS undergo blood tests every 3–6 months (6), experts did not consider that blood-based NfL determination could introduce any additional risk or extra costs.

According to the experts, the quantification of blood-based NfL may have the potential to positively influence the overall quality of life of patients with MS by enabling more effective disease monitoring, thereby enhancing the possibility of improved health outcomes. Moreover, it could help patients maintain their emotional well-being, and integrating blood-based NfL quantification into MS management may provide significant benefits, as they may perceive a better control of their disease. It can give patients a greater sense of security as they could know they do not have neuronal inflammation, despite the uncertainties associated with their conditions.

Regarding the costs associated with the use of blood-based NfL as a biomarker, experts considered that it could result in both direct and indirect cost savings. The panel considered that incorporating blood-based NfL into MS clinical practice could have the potential to reduce the need for more expensive tests, such as MRI scans, thereby optimizing resource utilization. Considering that patients with MS already undergo periodic blood tests, the integration of blood-based NfL would not impose any additional burden on patients or hospitals in this regard. Furthermore, the expert panel emphasized the importance of refining treatment selection and the potential value of blood-based NfL in facilitating the early identification of non-responders, ultimately mitigating medical costs linked to ineffective treatments (44). The panel also agreed on the potential value of blood-based NfL in reducing indirect costs associated with MS. Quantification of blood-based NfL provides more information about blood-based NfL, facilitating a better control and likely reducing indirect costs associated with disease management. It has the potential to act as a preventive measure against disease progression and mitigate the overall consequences of disability, likely enhancing productivity among patients. This is especially relevant in young patients (45). The main economic limitation identified in blood-based NfL quantification was the initial investment required for laboratory equipment. However, it was stated that as the technique becomes more widely adopted, the costs associated with equipment purchase could decrease. Indeed, some hospitals already possess the technology required, with a potentially cost-effective analysis per sample. Overall, the panel concluded that with the upcoming development and investment, the long-term benefits and potential cost savings make blood-based NfL extraction a viable and economical choice as a biomarker in MS.

The incorporation of blood-based NfL measurement for MS is inadequately represented in clinical practice guidelines in Spain or globally at the time of this study (39, 46). The quantification of blood-based NfL is a novel and innovative approach that is currently being explored for potential inclusion in broader clinical recommendations. Nevertheless, experts unanimously affirmed that, within the neurological scientific community, there is clear endorsement of the utility of blood-based NfL quantification in MS despite this limited inclusion in guidelines.

However, it is important to note that, when evaluating individual blood-based NfL levels, it is necessary to consider several factors, including the influence of various pathophysiological variables such as renal function, blood volume, and body mass index (BMI). Understanding how these factors can impact blood-based NfL levels is essential for accurate interpretation of results and make more informed decisions (18). Thus, the use of a standardized score (z-score), indicating the age and BMI-adjusted standard deviations of blood-based NfL levels from a dataset of healthy donors (16), improves interpretation of blood-based NfL concentrations at an individual level. Potential modifications of this z-score might be warranted in the future, depending on whether additional variables influencing blood-based NfL values are further described.

MCDA methodology has been employed in recent studies to assess the value contribution of a health technology in a range of medical conditions. Additionally, it functions as a valuable tool for Health Technology Agencies and pharmacotherapeutic committees, facilitating evaluations and decision-making processes. Using MCDA methodology enables a comprehension of the perceived value of a new health technology, achieved through the scoring of the evidence matrix, considering a diverse range of value attributes (33–35). It is therefore understandable that MCDA methodology is becoming increasingly popular to support healthcare decision-making, particularly in complex cases (26–28, 31, 32).

The present study is not exempt from some limitations (35). First, the participation of a relatively small number of experts may introduce potential bias. The decision to opt for a modest panel size in the MCDA exercises was deliberate, aiming to foster active participation in group discussions and encourage the sharing of diverse perspectives, facilitating a more in-depth analysis of the various value criteria under consideration. Second, the results may be affected by the composition of the expert panel, their value judgements, and their experience. Participants received training on MCDA methodology prior to the individual scoring work and discussion session to mitigate the risk of expertise bias.

To our knowledge, this is the first study to apply MCDA methodology to establish the overall value contribution of blood-based NfL as a biomarker in MS. The findings suggest that blood-based NfL quantification in MS represents a high-value option for determining disease activity, neurodegeneration, and response to treatment, from the experts’ perspective. MCDA has demonstrated to be useful to compare the value of health technologies in MS, allowing analysis and reflective discussion in a systematic, objective, pragmatic and transparent way from the point of view of key stakeholders involved in the management of MS.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

EM: Writing – review & editing. PR: Writing – review & editing. IS: Writing – review & editing. AR-A: Writing – review & editing. MM-M: Writing – review & editing. AÁ: Writing – review & editing, Conceptualization. EG-A: Conceptualization, Writing – review & editing. JM: Conceptualization, Writing – review & editing. JS: Writing – review & editing. ÁC: Writing – original draft. LV: Writing – review & editing.