A systemic search was conducted from electronic databases. Effect of Fingolimod on NfL levels was analysed qualitatively. Five Randomized Controlled Trials, including 5025 MS-patients, were used in the meta-analysis «Ashkar A, Baig MMA, Arif A, ym. Prognostic signifi...»1. Three studies were from Switzerland «Kuhle J, Kropshofer H, Haering DA, ym. Blood neuro...»2, «Häring DA, Kropshofer H, Kappos L, ym. Long-term p...»3, «Leppert D, Kropshofer H, Häring DA, ym. Blood Neur...»4, one from Italy «Sormani MP, Haering DA, Kropshofer H, ym. Blood ne...»5 and one from United Kingdom «Kuhle J, Disanto G, Lorscheider J, ym. Fingolimod ...»6. The average age from these studies was 38 years.
Sormani et al. «Sormani MP, Haering DA, Kropshofer H, ym. Blood ne...»5 showed that there was 35% reduction in NfL when Fingolimod was used as compared to placebo which was 5.4% ( p < 0.001). Similarly, Leppert et al. «Leppert D, Kropshofer H, Häring DA, ym. Blood Neur...»4 showed a significant reduction of NfL of 9.1% in INFORMS trial. While there was an exponential reduction of 40% by month 12 in NfL levels, by Häring et al. «Häring DA, Kropshofer H, Kappos L, ym. Long-term p...»3 in its NfL subset. Furthermore, two studies were conducted by Kuhle et al. «Kuhle J, Disanto G, Lorscheider J, ym. Fingolimod ...»6, «Kuhle J, Kropshofer H, Haering DA, ym. Blood neuro...»2, both of which showed statistically significant reduction in NfL levels when patients were treated with Fingolimod vs placebo.
A strong correlation was recorded for NfL levels and percentage of brain volume change, new/active T2 lesions and relapses. In addition, a statistically significant effect of NfL on cognitive disability worsening. Since the data is collected in each study for longer intervals of time i.e., 6 months/12 months/24 months, long term effect of fingolimod on NfL is obtained. Fingolimod proves itself as an important therapeutic agent by reducing the levels of NfL in blood/serum and cerebrospinal fluid «Ashkar A, Baig MMA, Arif A, ym. Prognostic signifi...»1.
The Immunomodulation and Multiple Sclerosis Epidemiology study (IMSE) is a comprehensive nationwide Swedish postapproval program of patients starting newer MS DMTs, coupled with sampling of blood at initiation of therapy and at follow-up (absolute range 4–24 months). 1,139 patients with RRMS initiated alemtuzumab (ALM, n = 89), dimethyl fumarate (DMF, n = 339), fingolimod (FGL, n = 275), natalizumab (NTZ, n = 284), or teriflunomide (TFL, n = 152) with median ages of 33, 42, 38, 37, 39, 45 respectively. For all analyses, pNfL levels were log-transformed to increase the normality of the distribution and normalized to age 40 (log-pNfLN40), by using the linear relationship between increasing log-pNfL and age in a large population-based control sample. To describe changes, unweighted means of the log-pNfLN40 across different DMTs were used, and subsequently, values were weighted by the inverse of the propensity scores. The mean change was affected by the type of DMT, with the largest mean reduction for ALM in both analyses; 54% reduction [95% CI 43%–62% reduction] and 48% reduction [49%–56% reduction] respectively for the unweighted and weighted analyses and the smallest change for TFL, for which the significance level of 0.05 was not reached; 12% increase [3% reduction to 29% increase] and 7% reduction [16% reduction to 4% increase] respectively for the unweighted and weighted analyses. For DMF reduction was 35% [32-45% reduction] and 26% [13-37% reduction]. For FGL reduction was 38% [27%-48% reduction] and 36% [24%-45% reduction]. The mean delta between DMF and FGL and between NTZ and ALM were not statistically different for the unweighted model. In the weighted model, the mean delta of NTZ did not differ significantly from DMF and FGL. Finally, is was observed that the changes in log-pNfLN40 values, correlated with improvements in clinical variables, such as EDSS, MSSS, and MSIS-29 «Delcoigne B, Manouchehrinia A, Barro C, ym. Blood ...»7.
For derivation of a reference database of serum neurofilament light values, a control group (10 133 blood samples from 5390 people) was created, comprising participants with no evidence of CNS disease taking part in four cohort studies in Europe and North America. 1313 MS patients (mean age 40.5 years, females 67.3%), with a disease course classified as relapsing (94.3%) or secondary progressive (5.7%), were participants with multiple sclerosis in the Swiss Multiple Sclerosis Cohort (SMSC). At entry into the SMSC, 376 (28·6%) people were untreated, 169 (12·9%) were on platform compounds (interferons [64.5%] and glatiramer acetate [35.5%]), 453 (34·5%) were on oral therapies (dimethyl fumarate [26.2%], fingolimod [66.0%], siponimod [0.6%], and teriflunomide [7.3%]), and 303 (23·1%) were on high efficacy monoclonal antibody therapy (alemtuzumab [2.9%], natalizumab [45.8%], ocrelizumab [31.2%], and rituximab [20.2]). Over a median follow-up period of 5·6 (IQR 3·2–7·2) years, 121 (9·2%) of 1313 individuals remained untreated, 788 people (60·0%) were treated with one compound from these disease-modifying therapy classes, and 404 people (30·8%) were treated with more than one class of disease-modifying therapy. A total of 7769 serum samples were obtained with a median number of samples per person of 6.0. A sNfL Z score above 1.5 was associated with an increased risk of future clinical or MRI disease activity in all people with MS (odds ratio 3·15, 95% CI 2·35-4·23; p<0·0001) and in people considered stable with no evidence of disease activity (2·66, 1·08-6·55; p=0·034). A conservative cutoff of 10 pg/mL was used as an arbitrary definition of a non-pathological sNfL concentration. Using three different threshold levels for high and low samples, increased sNfL Z scores and absolute sNfL concentrations both showed a higher likelihood for disease activity in the following year (EDA-3; p<0·0001). However, Z scores consistently led to higher ORs than did absolute sNfL values when using the three different cutoffs for a sample defined as high (ie, top 25%, top 10%, and top 5%). For ORs of absolute sNfL concentrations versus sNfL Z scores, the top 25% resulted in ORs of 2·09 vs 3·09; the top 10% in 2·83 vs 3·84; and the top 5% in 2·53 vs4·43, which corroborates the superior performance of sNfL Z scores over fixed cutoff levels of absolute sNfL values. The reduction of the sNfL Z score was more rapid with high efficacy monoclonal antibody therapies, compared with oral therapies and platform compounds, as reflected by the steeper slope of the line (p<0·0001 for the interaction term between treatment category and treatment duration). Over the following 4 years, high efficacy monoclonal antibody therapies and, to a lesser extent, oral therapies showed sNfL concentrations that overlapped with those of the control population (ie, sNfL Z score 0), whereas with platform compounds the sNfL concentrations remained increased, p<0·0001. Results were fully supported in the validation cohort (n=4341) from the Swedish Multiple Sclerosis registry «Benkert P, Meier S, Schaedelin S, ym. Serum neurof...»8.
This multicenter cohort study «Monreal E, Fernández-Velasco JI, García-Sánchez MI...»9 included patients who underwent their first demyelinating event suggestive of MS at Hospital Universitario Ramón y Cajal (development cohort; June 1, 1994, to September 31, 2021, with follow-up until August 31, 2022) and 8 Spanish hospitals (validation cohort; October 1, 1995, to August 4, 2020, with follow-up until August 16, 2022). Patients were diagnosed with clinically isolated syndrome (8.1%) or MS based on the 2017 revisions of the McDonald criteria. Of the 578 patients included in the study, 327 were in the development cohort (median age at sNfL analysis, 34.1 years [IQR, 27.2-42.7 years]; 226 female [69.1%]) and 251 patients were in the validation cohort (median age at sNfL analysis, 33.3 years [IQR, 27.4-41.5 years]; 184 female [73.3%]). The median follow-up was 7.1 years (IQR, 4.2-10.0 years). Levels of sNfL were measured in blood samples obtained within 12 months after first relapse. Disease-modifying treatments (DMTs) were divided in 2 categories: high-efficacy DMTs (natalizumab, alemtuzumab, ocrelizumab, rituximab, ofatumumab and mitoxantrone) and others. The cutoff value for sNfL concentrations was established as 10 pg/mL. A standardized score (z score) value of 1.5 was also a cutoff reflecting the age and body mass index–adjusted SDs of sNfL levels from a normative data set of healthy controls. Levels of sNfL greater than 10 pg/mL were independently associated with higher risk of 6-month confirmed disability worsening (CDW) and an EDSS of 3. In contrast, highly effective DMTs were associated with lower risks of 6-month CDW and an EDSS of 3 even in patients with high baseline sNfL values.
Comment: Results were more specific when blood samples were obtained at least 60 or 90 days after a relapse. Usually it takes about 2-3 months after relapse to establish MS-diagnosis and initiate treatment.
Canto et al 2019 «Cantó E, Barro C, Zhao C, ym. Association Between ...»10 studied neurofilament light levels in serum (sNfL, serum neurofilament light) and its association with disease course in patients with MS in 12 years follow-up. 607 patients participating in the EPIC (Expression, Proteomics, Imaging, Clinical) study in US were recruited. Clinical study and sample collection was performed annually for five years, then patients were followed for ten years (quartiles 7-11 yrs). Primary endpoints were increment of EDSS-score and brain atrophy in imaging. Mean age for study patients ws 42.5 (SD 9.8) yrs and 423 (69.7%) patients were women. 3904 serum sNfL samples were obtained. SNfL levels in the starting point were significantly associated with EDSS-scores (β, 1.080, 95%CI, 1.047-1.114, p<0.001), the type of MS (β, 1.478, 95%CI, 1.279-1.707, p<0.001) as well as the phase of treatment (β, 1.120, 95%CI, 1.007-1.245, p=0.04). Significant association was observed with increment in EDSS-score and sNfL levels with time (β, 1.015, 95%CI, 1.007-1.023, p<0.001). Active treatment was associated with lower sNfL levels and high efficacy treatment was associated with higher decrements in the sNfL levels in five years follow-up, compared to platform therapies (high efficacy therapy vs. no therapy: β, 0.946, 95%CI, 0.915-0.976, p<0.001, high efficacy therapy vs. platform therapy β, 0.972, 95%CI, 0.948-0.998, p=0.04).
Data for this study «Sotirchos ES, Fitzgerald KC, Singh CM, ym. Associa...»11 were collected as part of the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network between November 2016 and May 2021. Serum samples were available for 7246 PwMS and 201 HC. Samples from 272 MS participants were excluded due to insufficient quantity of serum in the aliquots (n = 204) or excessive hemolysis (n = 68), leaving 6974 MS participants (CIS/RRMS 70%, progressive 30%, mean age 46.9, sNfL median [IQR] 11.1 pg/mL [8.4, 14.8]) with samples available for sNfL measurement. DMT class was known for 6625 patients: IFN-b/GA (IFN-b n = 611; GA n = 762), Oral (Fumarate n = 1054; S1P inhibitor n = 874; Teriflunomide n = 285), Infusion/IRT (anti-CD20 n = 943; Natalizumab n = 684; Alemtuzumab n = 89; Daclizumab n = 10; Cladribine n = 3). A small proportion of participants (n = 47) reported use of oral immunosuppressive medications (including mycophenolate, methotrexate, cyclosporine, or cyclophosphamide) or intravenous immune globulin (n = 7). Analyses were performed using the age-normative sNfL Z-score as a continuous variable (truncated at the 99.9th percentile), as well as using a pre-defined Z-score cut-off of 1.96 (97.5th centile curve) to define "elevated" (sNfL-E) versus "normal" sNfL (sNfL-N). Estimated glomerular filtration rate (eGFR) was calculated using the creatinine value (if available) closest to the date of blood sampling for sNfL measurement, using the CKD-EPI 2021 equation incorporating age and sex, omitting race, and was categorized as >90 ("normal"), 60–90 ("mildly impaired), and <60 mL/min/1.73 m2 ("moderately to severely impaired"). Body mass index (BMI) was categorized as <18.5 ("underweight"), 18.5–24.0 ("reference"), 25.0–29.9 ("overweight"), 30.0–39.9 ("obese"), and ≥ 40 ("morbidly obese"). Use of an MS DMT was associated with lower odds of elevated sNfL, in multivariaty analysis, although 70% of patients with elevated sNfL were on an MS DMT: IFN-b/GA 0.63 CI (0.50, 0.78, <0.001), Infusion/IRT 0.63 CI (0.51, 0.77, p <0.001), Oral 0.45 CI (0.37, 0.55, p <0.001), Other or unknown 0.78 CI (0.61, 1.01, p=0.060). In addition, factors associated with increased odds of elevated sNfL included male sex (adjusted OR: 1.20, 95% CI: 1.04 to 1.39, P = 0.012), progressive disease subtype (adjusted OR: 1.63, 1.41 to 1.88, P < 0.001), diabetes mellitus (adjusted OR: 1.67, 95% CI: 1.31 to 2.12, P < 0.001), current smoking (adjusted OR: 1.21, 95% CI: 1.02 to 1.43, P = 0.029), and moderately to severely decreased eGFR (adjusted OR 5.21; 95% CI: 3.39 to 8.0, P < 0.001). Overall, higher age was associated with lower odds of elevated sNfL compared to younger patients (reference age group: 18–38 years). Individuals with short (<5 years) or long (>23 years) disease duration had higher odds of elevated sNfL compared to other disease duration categories. Increasing BMI was associated with lower odds of elevated sNfL, and this association was consistent across BMI categories.