Fluid biomarkers: theory and practice


ACTRIMS Forum 2024

Considerable progress has been made in recent years in determining the place in therapy of fluid biomarkers of multiple sclerosis and other neurological disorders. Among the most studied are neurofilament-light chain (NfL), a marker of neuroaxonal damage, and glial fibrillary acidic protein (GFAP), a marker of astrogliosis. The following summarizes fluid biomarker studies presented at the Americas Committee for Treatment and Research in MS (ACTRIMS) Forum, held February 29 to March 2, 2024, in West Palm Beach, Florida.

A study in India examined the prognostic value of baseline sNfL concentration in 129 patients (median age 33 years, median EDSS 3.0) with relapsing and progressive MS (Kaur et al. ACTRIMS Forum 2024;P062). The median sNfL concentration was 11.6 pg/mL in RRMS, 17.1 pg/mL in SPMS and 14.5 pg/mL in PPMS. Median sNfL concentrations were higher in untreated versus treated patients (15.6 vs. 11.4 pg/mL. RRMS patients with a baseline sNfL level <8.04 pg/mL were significantly less likely to progress to SPMS compared to patients with a higher baseline concentration.

The prognostic value of baseline sNfL was demonstrated in the ASCLEPIOS I/II trials of ofatumumab, which reported a significantly higher annualized rate of new/emerging T2 lesions in patients with the highest versus lowest baseline sNfL (Hauser et al. N Engl J Med 2020;383:546-557). The cut-off value for high versus low sNfL was 9.3 pg/mL. A subsequent analysis of the ASCLEPIOS cohort reported that the prognostic value of baseline sNfL was evident across all ethnic/racial subgroups studied, including Caucasian (relative risk 3.91), Black (RR 2.50) and Asian (RR 2.68) (Delgado et al. ACTRIMS Forum 2024;P036). A higher vs. lower baseline sNfL was also prognostic of new/enlarging T2 lesions when stratified by age (<38 years, RR 1.95; >38, RR 2.66) and body-mass index (<24.5 kg/m2, RR 1.92; ≥ 24.5 kg/m2, RR 2.49) (Cross et al. ACTRIMS Forum 2024;P037).

Serial assessment may also be clinically useful since NfL retains its predictive value during treatment. In a separate analysis of ASCLEPIOS I/II, patients with higher vs. lower sNfL concentrations during treatment had a higher risk (2.2-fold higher at 3 months, 3.6-fold higher at 12 months) of new/enlarging T2 lesions (Leist et al. ACTRIMS Forum 2024;P032).

An emerging approach is to evaluate NfL as part of a biomarker panel of proteins associated with MS disease activity. An example is the Octave MS Disease Activity (MSDA) panel, which assesses NfL and 17 other proteins, such as MOG, CD6, CXCL13 and IL12B. Octave was used in a retrospective study of 173 MS patients receiving a lower-efficacy (interferon-β, glatiramer acetate), moderate-efficacy (teriflunomide, dimethyl fumarate, S1PR agents) or higher-efficacy DMT (natalizumab, anti-CD20 MAbs) (Chumakova et al. ACTRIMS Forum 2024;P058). There were significant differences in MSDA score in patients on no treatment or a lower-efficacy DMT compared to those on a moderate- or higher-efficacy DMT. Score differences were primarily due to markers for disease pathways associated with neuroinflammation, immunomodulation and myelin biology.

A separate study using the Octave MSDA panel reported that immune profiling was a useful indicator of recent disease activity (Izbicki et al. ACTRIMS Forum 2024;P051). The panel was used in 90 consecutive MS patients; mean age was 43 years, mean EDSS score was 3.97. The mean MSDA score was 4 of 10. Eleven of the 12 patients with high MSDA scores had clinical or MRI evidence of recent disease activity; two patients had a high score prior to clinical or radiological evidence of disease activity.

Canadian researchers investigated the utility of a panel of antiphospholipid antibodies (aPL) to differentiate MS subtypes (Frese et al. ACTRIMS Forum 2024;P064). PLs were examined since lipids (cholesterol, phospholipids, glycolipids, sphingomyelin) are released during demyelination. Serum IgM was analysed in CIS (n=20), RRMS (n=33), PMS (n=50) and healthy controls (n=35). IgM levels to all phospholipids were elevated in CIS compared to controls. IgM aPLs were elevated for only two of the phospholipids examined (phosphatidyl-inositol [PI] and -serine [PS]) in RRMS patients versus controls. Higher IgM to cardiolipin, sphingomyelin (SM), PI and PS was associated with a greater risk of SPMS rather than RRMS. Elevated PI, PS, SM and phosphatidyl-ethanolamine aPL were prognostic of a higher EDSS score in PPMS patients; however, elevated SM, PI, PS and CL aPL were inversely associated with EDSS in SPMS. The authors noted that IgM response to a range of PLs appeared more relevant than a response to an individual PL. A higher number of aPL responses differentiated CIS/MS from controls, and SPMS from RRMS or PPMS.

Incorporating NfL use into practice
The NeofiLos study is currently examining the routine use of sNfL testing in 80 community neurology practices in Germany (Akgun et al. ACTRIMS Forum 2024;P033). According to the interim survey results, 90.7% of neurologists would use sNfL testing in routine clinical practice. The most common reasons for testing were to complement clinical/MRI assessments of disease activity (90.7% of respondents), as an additional prognostic factor (82.4%), to classify disease activity (76.8%), for treatment decision-making (73.6%), and to monitor disease activity (72.4%). The preferred timing of sNfL testing was at diagnosis (83.9%), during monitoring of treatment response (86.8%), and when starting (78.2%) or switching (77.5%) DMTs. The preferred frequency of testing was every 6-12 months (45.0%) or every 3-6 months (36.2%). Most respondents (75.6%) said they would reconsider their current treatment selection if sNFL levels were elevated. However, before sNfL testing is more widely adopted in clinical practice, most neurologists said they would like to see usage recommendations in clinical practice guidelines (66.3%) or from a professional society (59.7%), or to have more own clinical experience with testing (54.8%).

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