It has long been known that tumour necrosis factor (TNF)/TNFRSF1A signalling is involved in the pathophysiology of multiple sclerosis (MS). Different genetic and clinical findings over the last few years have generated renewed interest in this relationship. This paper provides an update on these recent findings. Genome-wide association studies have identified the R92Q mutation in the TNFRSF1A gene as a genetic risk factor for MS (odds ratio 1·6). This allele, which is also common in the general population and in other inflammatory conditions, therefore only implies a modest risk for MS and provides yet another piece of the puzzle that defines the multiple genetic risk factors for this disease. TNFRSF1A mutations have been associated with an autoinflammatory disease known as TNF receptor-associated periodic syndrome (TRAPS). Clinical observations have identified a group of MS patients carrying the R92Q mutation who have additional TRAPS symptoms. Hypothetically, the co-existence of MS and TRAPS or a co-morbidity relationship between the two could be mediated by this mutation. The TNFRSF1A R92Q mutation behaves as a genetic risk factor for MS and other inflammatory diseases, including TRAPS. Nevertheless, this mutation does not appear to be a severity marker of the disease, neither modifying the clinical progression of MS nor its therapeutic response. An alteration in TNF/TNFRS1A signalling may increase proinflammatory signals; the final clinical phenotype may possibly be determined by other genetic or environmental modifying factors that have not yet been identified.

In multiple sclerosis (MS), half of affected people are unemployed within 10 years of diagnosis. The aim of this study was to assess the economic impact of MS in adult subjects with relapsing-remitting MS (RRMS) and primary progressive MS (PPMS). A multicenter, non-interventional, cross-sectional study was conducted. The Expanded Disability Status Scale (EDSS) and the 23-item Multiple Sclerosis Work Difficulties Questionnaire (MSWDQ-23) were used to assess disability and work performance, respectively. Only indirect costs were considered using the human capital method, including work costs. Professional support costs and informal caregivers’ costs were also estimated. A total of 199 subjects were studied (mean age: 43.9 ± 10.5 years, 60.8% female, 86.4% with RRMS). Median EDSS score was 2.0 (interquartile range: 1.0–3.5) and median MSWDQ-23 total score was 31.5 (15.2, 50.0). The number of employed subjects decreased after MS diagnosis from 70.6 to 47.2%, and the number of retired people increased (23.6%). Mean age of retirement was 43.6 ± 10.5 years. Ten percent of the population had sick leaves (absenteeism was seen in 90.9% of the student population and 30.9% of the employed population). Professional support in their daily life activities was needed in 28.1% of subjects. Costs for sick leave, work absenteeism, premature retirement and premature work disability/pensioner were €416.6 ± 2030.2, €763.4 ± 3161.8, €5810.1 ± 13,159.0 and €1816.8 ± 9630.7, respectively. Costs for professional support and informal caregiving activities were €1026.93 ± 4622.0 and €1328.72, respectively. MS is responsible for a substantial economic burden due to indirect and informal care costs, even in a population with low physical disability.

Objective To understand COVID-19 characteristics in people with multiple sclerosis (MS) and identify high-risk individuals due to their immunocompromised state resulting from the use of disease-modifying treatments. Methods Retrospective and multicenter registry in patients with MS with suspected or confirmed COVID-19 diagnosis and available disease course (mild = ambulatory; severe = hospitalization; and critical = intensive care unit/death). Cases were analyzed for associations between MS characteristics and COVID-19 course and for identifying risk factors for a fatal outcome. Results Of the 326 patients analyzed, 120 were cases confirmed by real-time PCR, 34 by a serologic test, and 205 were suspected. Sixty-nine patients (21.3%) developed severe infection, 10 (3%) critical, and 7 (2.1%) died. Ambulatory patients were higher in relapsing MS forms, treated with injectables and oral first-line agents, whereas more severe cases were observed in patients on pulsed immunosuppressors and critical cases among patients with no therapy. Severe and critical infections were more likely to affect older males with comorbidities, with progressive MS forms, a longer disease course, and higher disability. Fifteen of 33 patients treated with rituximab were hospitalized. Four deceased patients have progressive MS, 5 were not receiving MS therapy, and 2 were treated (natalizumab and rituximab). Multivariate analysis showed age (OR 1.09, 95% CI, 1.04–1.17) as the only independent risk factor for a fatal outcome. Conclusions This study has not demonstrated the presumed critical role of MS therapy in the course of COVID-19 but evidenced that people with MS with advanced age and disease, in progressive course, and those who are more disabled have a higher probability of severe and even fatal disease.

Introduction Teriflunomide is a once-daily oral immunomodulator approved for relapsing forms of multiple sclerosis (MS) or relapsing–remitting multiple sclerosis (RRMS; depending on the local label), based on extensive evidence from clinical trials and a real-world setting on efficacy, tolerability and patient-reported benefits. The TERICARE study assessed the impact of teriflunomide treatment over 2 years on health-related quality of life (HRQoL) and some of the most common and disabling symptoms of MS, such as fatigue and depression. Methods This prospective observational study in Spain included RRMS patients treated with teriflunomide for ≤ 4 weeks. The following patient-reported outcomes (PROs) were collected at baseline and every 6 months for 2 years: the 29-item Multiple Sclerosis Impact Scale version 2 (MSIS-29), the 21-item Modified Fatigue Impact Scale (MFIS-21), the Beck Depression Inventory (BDI-II), the Short Form (SF)-Qualiveen and the Treatment Satisfaction Questionnaire for Medication v1.4 (TSQM). Annualised relapse rate (ARR), disability progression according to the Expanded Disability Status Scale (EDSS), and no evidence of disease activity (NEDA-3) were also assessed. Results A total of 325 patients were analysed. Patients had a mean (SD) age of 43.2 years (10.4), a mean baseline EDSS score of 1.75 (1.5), a mean number of relapses in the past 2 years of 1.5 (0.7), and 64% had received prior disease-modifying therapy (DMT). Patients showed significant improvements in the psychological domain of MSIS-29 from 35.9 (26.6) at baseline to 29.4 (25.5) at 18 months (p = 0.004) and 29.0 (24.6) at 24 months (p = 0.002). Levels of fatigue and depression were also reduced. After 2 years of treatment with teriflunomide, ARR was reduced to 0.17 (95% CI 0.14–0.21) from the baseline of 0.42 (95% CI 0.38–0.48), representing a 60.1% reduction. Mean EDSS scores remained stable during the study, and 79.9% of patients showed no disability progression. 54.7% of patients achieved NEDA-3 in the first 12 months, which increased to 61.4% during months 12–24. Patients reported increased satisfaction with treatment over the course of the study, regardless of whether they were DMT naive or not. Conclusion Teriflunomide improves psychological aspects of HRQoL and maintains low levels of fatigue and depression. Treatment with teriflunomide over 2 years is effective in reducing ARR and disability progression.

Serum neurofilament light chain (sNfL) is an analytically robust blood-based biomarker of recent neuroaxonal injury in multiple sclerosis (MS), supported by validated ultrasensitive immunoassays suitable for routine measurement. These assays now enable reliable measurement in routine care, and evidence links higher levels and rising trajectories to inflammatory activity, treatment response, and—at a population level—future tissue loss and disability risk. Clinical implementation is constrained by overinterpretation of single measurements: sNfL is not MS-specific, is strongly age-dependent, is influenced by systemic and neurological confounders, and reflects injury over weeks to months rather than cumulative neurodegeneration. This review proposes a clinically oriented framework in which sNfL serves as decision support alongside MRI and clinical assessment, not as a stand-alone trigger for therapy changes. We prioritize longitudinal interpretation anchored to an individual baseline or nadir, the use of age-adjusted reference frameworks (percentiles or Z-scores where available), standardization of key pre-analytical and analytical conditions, and structured approaches to discordance between biomarkers, imaging, and symptoms. We discuss the complementary role of serum glial fibrillary acidic protein (sGFAP) as a marker of chronic astroglial pathology and progression-dominant biology, and how combined biomarker patterns may refine interpretation when disability worsens despite limited inflammatory activity. Across the MS continuum—from prodromal states and radiologically isolated syndrome to relapsing and progressive phenotypes—we summarize practical use cases, limitations, and safety-critical “red flags” where marked sNfL surges warrant urgent reassessment. Finally, we highlight consensus-based implementation principles and research priorities, including pragmatic trials to test whether biomarker-informed strategies improve patient-relevant outcomes.

Background: Cognitive impairment has an impact upon the function and quality of life of patients with multiple sclerosis (MS). High-serum neurofilament light-chain (sNfL) levels predict disease progression and are also associated with impaired cognitive performance. This study aimed to assess the attitudes of neurologists toward sNfL testing as regards making therapeutic decisions in clinically and radiologically stable patients experiencing cognitive decline. Methods: A web-based observational study was conducted among neurologists caring for patients with MS. The role of sNfL in therapeutic decisions was assessed through a simulated case scenario describing a 31-year-old woman with relapsing–remitting MS for four years on glatiramer acetate. Her partner reported increased distractibility and difficulties in organizing daily activities over the past 18 months. There was no history of new relapses, and a follow-up brain MRI scan showed no new lesions. Her performance in the Symbol Digit Modalities Test decreased by 8 points from the previous year, with 46 correct answers. The patient had an sNfL level of 21 pg/mL, with no other identified factors that could have altered this value. The participants were tasked with deciding to either escalate treatment or to continue the current treatment and schedule the patient for reassessment in 6–12 months (defined as decisions misaligned with emerging evidence [DMEE]). Multivariate regression analysis was conducted to determine factors associated with DMEE. Results: One hundred and sixteen neurologists participated in the study. Almost 50% of the participants (n = 57) opted not to escalate treatment despite high sNfL levels. This was more common among neurologists not fully dedicated to MS care (60.5% vs. 43.6%). The multivariate analysis showed that being a neurologist not fully dedicated to MS (odds ratio [OR] = 2.35, 95% confidence interval [CI] 1.01–5.50; p = 0.04) and having a poor perception of sNfL benefits (OR = 1.02, 95% CI 1.00–1.04; p = 0.01) were associated with DMEE. Conclusions: Neurologists’ lack of full dedication to MS care and limited perception of sNfL’s clinical utility were key factors associated with suboptimal therapeutic decisions in a simulated case of cognitive decline with elevated sNfL. These findings underscore the need for increased education on the role of sNfL to improve evidence-based decision-making in MS management.