Biomarkers – evolving role of neurofilament light
Neurofilament light (NfL) is emerging as an important biomarker of axonal damage. Single-molecule array (Simoa) technology has enabled sampling of blood rather than CSF, broadening NfL research into neurological conditions in which lumbar puncture is not routinely performed. The prognostic value of NfL was evaluated in a study of 3765 MS patients and 1026 controls over a 5-year period (Manouchehrina et al. ECTRIMS 2018; abstract P378). The risk of reaching EDSS 3.0 was increased by 33% in MS patients with plasma NfL levels >50th healthy controls percentile; risk was increased 61% with levels >75th percentile.
Three studies examined the association between NfL and cognitive impairment. A small Italian study reported a correlation between serum NfL and Cognitive Impairment Index scores, memory and executive function; higher NfL levels were associated with more severe cognitive impairment (Mattioli et al. ECTRIMS 2018; abstract P458). A 9-year follow-up study found an association between baseline NfL levels and verbal memory decline, and a trend to a decline in PASAT-3 scores at 9 years (Uher et al. ECTRIMS 2018; abstract P530). A separate study found NfL levels in CSF were higher in MS patients with global cognitive impairment; the domains most affected were information processing speed and verbal fluency (Gaetani et al. ECTRIMS 2018; abstract P536).
A novel study examined NfL in monozygotic twins with and without MS (Gerdes et al. ECTRIMS 2018; abstract P853). Serum NfL levels were significantly lower in healthy versus MS twins. Interestingly, NfL was elevated in 13 of 54 healthy twins; further examination revealed evidence of subclinical inflammation in CSF, vascular MRI lesions, or cerebellar atrophy.
Two studies reported on NfL levels during treatment. The first obtained blood samples from >1000 patients enrolled in the ADVANCE (Peg-interferon-beta-1a), CHAMPS and MSCRG (interferon-beta-1a), and SENTINEL (natalizumab) trials (Calabresi et al. ECTRIMS 2018; abstract 158). Baseline NfL was associated with the number of Gd-enhancing lesions and the accumulation of new T2 lesions over time. NfL was higher in patients with active disease or high brain atrophy rates; levels were low in patients with no evidence of disease activity (NEDA). An NfL level >16 pg/mL was associated with a high risk of disease activity in the following year and poorer clinical/radiological outcomes over the long term. NfL was below the 16 pg/mL cut-off in 96% of natalizumab-treated patients. A separate retrospective study evaluated NfL changes in the 24-week RESTORE study (Tackenberg et al. Neurology 2015;84: 862), which randomized natalizumab-treated patients with no disease activity to continue on natalizumab or switch to another therapy (Fox et al. ECTRIMS 2018; abstract P532). NfL levels remained low independently of treatment in patients with no Gd+ lesions. The number of Gd+ lesions was associated with increasingly high NfL: median levels changed 29%, 135% and 503% in patients with 1-4, 5-10 and >11 Gd+ lesions. NfL levels peaked about 7 weeks after detection of a Gd+ lesion.
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Oral cladribine – two reports
A post-hoc analysis of the CLARITY trial has reported a significant reduction in severe relapses with oral cladribine versus placebo (Schippling et al. ECTRIMS 2018; abstract P549). The annualized relapse rate was 0.27 with cladribine 3.5 mg versus 0.63 with placebo (0.15 vs. 0.35 for qualifying relapses). Risk reduction was 57% (58% for qualifying relapses). There was a 62-63% reduction in severe relapses, defined as relapses leading to hospitalization or steroid treatment. Age at diagnosis and prior DMD use affected the relapse rate at week 96; disease duration had no effect on the relapse rate.
A separate post-hoc analysis stratified CLARITY patients according to age: 45 years (n=221; median 51.0 years) (Giovannoni et al. ECTRIMS 2018; abstract P1204). Oral cladribine 3.5 mg was associated with a significant reduction in relapses in both age groups – a 61% risk reduction in younger patients, and a 50% reduction in the older group. Moreover, the number of cumulative new Gd+ lesions and the T2 lesion number/scan were reduced in both age groups to a similar degree versus placebo.
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Vitamin D improves corticosteroid efficacy
A new study has examined serum 25(OH)D3 levels in relapsing MS patients who did or did not respond to a course of steroids (Bagnoud et al. ECTRIMS 2018; abstract 80). Patients resistant to corticosteroids had lower serum 25(OH)D levels, and reduced expression of the glucocorticoid receptor (GR) in T cells. In vitro studies have shown that GR protein expression in T cells is upregulated in a dose-dependent manner by vitamin D (Kassi et al. Cell Mol Life Sci 2016;73:4341-54). Moreover, the addition of vitamin D to a corticosteroid increased T cell apoptosis by 10% compared to steroid alone. Vitamin D has been shown to inhibit mammalian target of rapamycin (mTOR) signalling in T cells, and the authors reported that use of everolimus, an mTOR inhibitor, in EAE was even more effective than vitamin D in augmenting the efficacy of steroids.
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First visit influences patient satisfaction, treatment start
Patient satisfaction with the initial neurologist consultation and the duration of the visit will influence whether or not an MS patient starts treatment, according to a retrospective analysis of the Swiss MS Registry (Barin et al. ECTRIMS 2018; abstract P335). Data were analysed for 421 individuals with CIS, RRMS or SPMS. Overall, 54% of patients stated they were satisfied with the first consultation, 22% were neutral and 24% were not satisfied. The duration of the office visit was >30 minutes for 32%, 10-30 minutes for 42%, and < 10 minutes for 18%. Topics discussed were the nature of MS (67%) and DMDs (72%). A total of 19% of patients were not offered a treatment option, 22% were given one DMD option and 59% were presented with 2 or more options. Seventy percent started treatment within 3 months; 7% after 3 months; and 23% did not start a DMD. The factors associated with patients’ satisfaction with the first consultation included involvement in the choice of DMD, the number of topics discussed, the clarity of the diagnosis, and socioeconomic status. Patients were more likely to start treatment if they were satisfied with the visit, and if the neurologist spent >30 minutes with them.
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