Background:
Neurofilament light chain (NFL) is a cerebrospinal fluid (CSF) marker of neuroaxonal damage in multiple sclerosis (MS).
Objective:
To determine the correlation of NFL in CSF and ...serum/plasma, and in plasma after switching from injectable MS therapies to fingolimod.
Methods:
A first cohort consisted of MS patients (n = 39) and neurological disease controls (n = 27) where CSF and plasma/serum had been collected for diagnostic purposes. A second cohort (n = 243) consisted of patients from a post-marketing study of fingolimod. NFL was determined with Single Molecule Array (Simoa™) technology (detection threshold 1.95 pg/mL).
Results:
Mean NFL pg/mL (standard deviation (SD)) was 341 (267) and 1475 (2358) in CSF and 8.2 (3.58) and 17.0 (16.94) in serum from controls and MS, respectively. CSF/serum and plasma/serum levels were highly correlated (n = 66, rho = 0.672, p < 0.0001 and n = 16, rho = 0.684, p = 0.009, respectively). In patients starting fingolimod (n = 243), mean NFL pg/mL (SD) in plasma was reduced between baseline (20.4 (10.7)) and at 12 months (13.5 (7.3), p < 3 × 10−6), and levels remained stable at 24 months (13.2 (6.2)).
Conclusion:
NFL in serum and CSF are highly correlated and plasma NFL levels decrease after switching to highly effective MS therapy. Blood NFL measurement can be considered as a biomarker for MS therapy response.
Vitamin D deficiency is associated with an increased risk of multiple sclerosis (MS). However, its effect on the age of disease onset remains unclear. This study examines the relationship between ...serum 25-hydroxyvitamin D (25(OH)D) levels and age of first symptom onset among recently diagnosed MS patients. Serum 25(OH)D was measured from forty MS patients sampled near disease onset. After correcting seasonal variability, the association between 25(OH)D levels, along with other clinical measures such as IgG index, and age at MS onset was examined using multivariable linear regression. Serum 25(OH)D was not correlated with age at onset (P > 0.5). We observed bias among previously reported associations between 25(OH)D and MS disease measures resulting from non-random distribution of sampling by season. After correcting for seasonal 25(OH)D and other clinical measures, only CSF IgG index remained significantly associated with age at disease onset (β = - 5.35, P = 0.028). In summary, we observed no association between age at onset and serum 25(OH)D levels but observed a negative correlation with CSF IgG index, although this will require further investigation.
Dimethyl fumarate (DMF) is a first-line-treatment for relapsing-remitting multiple sclerosis (RRMS). The redox master regulator Nrf2, essential for redox balance, is a target of DMF, but its precise ...therapeutic mechanisms of action remain elusive. Here we show impact of DMF on circulating monocytes and T cells in a prospective longitudinal RRMS patient cohort. DMF increases the level of oxidized isoprostanes in peripheral blood. Other observed changes, including methylome and transcriptome profiles, occur in monocytes prior to T cells. Importantly, monocyte counts and monocytic ROS increase following DMF and distinguish patients with beneficial treatment-response from non-responders. A single nucleotide polymorphism in the ROS-generating NOX3 gene is associated with beneficial DMF treatment-response. Our data implicate monocyte-derived oxidative processes in autoimmune diseases and their treatment, and identify NOX3 genetic variant, monocyte counts and redox state as parameters potentially useful to inform clinical decisions on DMF therapy of RRMS.
Blood Neurofilament light chain (NfL) has been suggested as a promising biomarker in several neurological conditions. Since blood NfL is the consequence of leaked NfL from the cerebrospinal fluid, ...differences in individuals’ Body Mass Index (BMI) or blood volume (BV) might affect its correlation to other biomarkers and disease outcomes. Here, we investigated the correlation between plasma NfL, BMI, and BV in 662 controls and 2,586 multiple sclerosis cases. We found a significant negative correlation between plasma NfL, BMI/BV in both groups. Our results highlight the potential confounding effect of BMI/BV on associations between blood NfL and disease outcomes.
Genome-wide association studies implicate dysregulation of immune mechanisms in the pathogenesis of multiple sclerosis (MS). Particularly, polymorphisms in genes involved in T helper (TH) cell ...differentiation are associated with risk of developing MS. However, the underlying mechanism by which these risk alleles influence MS susceptibility has remained elusive. Initiation of neuroinflammation in animal models of MS has been shown to be dependent on TH cell-derived granulocyte-macrophage colony-stimulating factor (GM-CSF). We here report association of GM-CSF expression by human TH cells with MS disease severity. GM-CSF is strongly induced by interleukin 2 (IL-2). We show that an MS-associated polymorphism in the IL-2 receptor alpha (IL2RA) gene specifically increases the frequency of GM-CSF-producing TH cells. The IL2RA polymorphism regulates IL-2 responsiveness of naive TH cells and their propensity to develop into GM-CSF-producing memory TH cells. These findings mechanistically link an immunologically relevant genetic risk factor with a functional feature of TH cells in MS.
Objective
We aimed to study (1) to what extent the influence of low sun exposure on multiple sclerosis (MS) risk is mediated by low vitamin D levels; (2) whether low sun exposure or vitamin D ...deficiency act synergistically with HLA-DRB1*15:01 and absence of HLA-A*02:01.
Methods
We used two population-based case–control studies (7069 cases, 6632 matched controls). Subjects with different HLA alleles, sun exposure habits and vitamin D status were compared regarding MS risk, by calculating odds ratios (OR) with 95% confidence intervals (CI) employing logistic regression. Mediation analysis was used to identify the potential mediation effect of vitamin D on the relationship between low sun exposure and MS risk.
Results
Low sun exposure increased MS risk directly as well as indirectly, by affecting vitamin D status. The direct effect, expressed as OR, was 1.26 (95% CI 1.04–1.45) and the indirect effect, mediated by vitamin D deficiency, was 1.10 (95% CI 1.02–1.23). Of the total effect, nearly 30% was mediated by vitamin D deficiency. There was a significant interaction between low sun exposure and vitamin D deficiency (attributable proportion due to interaction 0.3, 95% CI 0.04–0.5) accounting for about 12% of the total effect. Further, both factors interacted with HLA-DRB1*15:01 to increase MS risk.
Interpretation
Our findings indicate that low sun exposure acts both directly on MS risk as well as indirectly, by leading to low vitamin D levels. The protective effect of sun exposure thus seems to involve both vitamin D and non-vitamin D pathways, which is of relevance for prevention, in particular for those with a genetic susceptibility to MS.
It is unclear whether smoking interacts with different aspects of Epstein-Barr virus (EBV) infection with regard to multiple sclerosis (MS) risk. We aimed to investigate whether smoking acts ...synergistically with elevated EBNA-1 antibody levels or infectious mononucleosis (IM) history regarding MS risk. Two Swedish population-based case-control studies were used (6,340 cases and 6,219 matched controls). Subjects with different smoking, EBNA-1 and IM status were compared regarding MS risk, by calculating odds ratios (OR) with 95% confidence intervals (CI) employing logistic regression. Potential interaction on the additive scale was evaluated by calculating the attributable proportion due to interaction (AP). Current and past smokers had higher EBNA-1 antibody levels than never smokers (p < 0.0001). There was an additive interaction between current smoking and high EBNA-1 antibody levels (AP 0.3, 95% CI 0.2-0.4), but not between past smoking and high EBNA-1 antibody levels (AP 0.01, 95% CI - 0.1 to 0.1), with regard to MS risk. An interaction also occurred between current smoking and IM history (AP 0.2, 95% CI 0.004-0.4), but not between past smoking and IM history (AP - 0.06, 95% CI - 0.4 to 0.3). Current smoking increases EBNA-1 antibody levels and acts synergistically with both aspects of EBV infection to increase MS risk, indicating that there is at least one pathway to disease in which both risk factors are involved.
Autoimmune thyroid disease is the most common autoimmune disease and is highly heritable
. Here, by using a genome-wide association study of 30,234 cases and 725,172 controls from Iceland and the UK ...Biobank, we find 99 sequence variants at 93 loci, of which 84 variants are previously unreported
. A low-frequency (1.36%) intronic variant in FLT3 (rs76428106-C) has the largest effect on risk of autoimmune thyroid disease (odds ratio (OR) = 1.46, P = 2.37 × 10
). rs76428106-C is also associated with systemic lupus erythematosus (OR = 1.90, P = 6.46 × 10
), rheumatoid factor and/or anti-CCP-positive rheumatoid arthritis (OR = 1.41, P = 4.31 × 10
) and coeliac disease (OR = 1.62, P = 1.20 × 10
). FLT3 encodes fms-related tyrosine kinase 3, a receptor that regulates haematopoietic progenitor and dendritic cells. RNA sequencing revealed that rs76428106-C generates a cryptic splice site, which introduces a stop codon in 30% of transcripts that are predicted to encode a truncated protein, which lacks its tyrosine kinase domains. Each copy of rs76428106-C doubles the plasma levels of the FTL3 ligand. Activating somatic mutations in FLT3 are associated with acute myeloid leukaemia
with a poor prognosis and rs76428106-C also predisposes individuals to acute myeloid leukaemia (OR = 1.90, P = 5.40 × 10
). Thus, a predicted loss-of-function germline mutation in FLT3 causes a reduction in full-length FLT3, with a compensatory increase in the levels of its ligand and an increased disease risk, similar to that of a gain-of-function mutation.
Human soluble interleukin-7 receptor (sIL7R)α circulates in high molar excess compared with IL-7, but its biology remains unclear. We demonstrate that sIL7Rα has moderate affinity for IL-7 but does ...not bind thymic stromal lymphopoietin. Functionally, sIL7Rα competes with cell-associated IL-7 receptor to diminish excessive IL-7 consumption and, thus, enhances the bioactivity of IL-7 when the cytokine is limited, as it is presumed to be in vivo. IL-7 signaling in the presence of sIL7Rα also diminishes expression of CD95 and suppressor of cytokine signaling 1, both regulatory molecules. Murine models confirm diminished consumption of IL-7 in the presence of sIL7Rα and also demonstrate a potentiating effect of sIL7Rα on IL-7–mediated homeostatic expansion and experimental autoimmune encephalomyelitis exacerbation. In multiple sclerosis and several other autoimmune diseases, IL7R genotype influences susceptibility. We measured increased sIL7Rα levels, as well as increased IL-7 levels, in multiple sclerosis patients with the predisposing IL7R genotype, consistent with diminished IL-7 consumption in vivo. This work demonstrates that sIL7Rα potentiates IL-7 bioactivity and provides a basis to explain the increased risk of autoimmunity observed in individuals with genotype-induced elevations of sIL7Rα.
Background:
Cognitive impairment occurs in 40%–70% of persons with multiple sclerosis (MS).
Objective:
To examine the effectiveness of natalizumab compared with other disease-modifying treatments ...(DMTs) on improving cognition as measured by the Symbol Digit Modalities Test (SDMT).
Methods:
Data were collected as part of Swedish nationwide phase IV surveillance studies (2007–2020). An increase in SDMT score by ⩾10% of the difference between maximum score possible (110) and the baseline value was defined as cognitive improvement. The likelihood of improvement was compared between natalizumab-treated individuals and individuals treated with other DMTs using mixed effect logistic regression. Trend in odds of improvement was investigated using slope analyses.
Results:
We included 2100 persons with relapsing-remitting MS treated with natalizumab and 2622 persons treated with other DMTs. At 6 months, 45% reached improvement. The natalizumab group showed largest odds of improvement during follow-up (odds ratio: 2.3, 95% confidence interval (CI): 1.5–3.5). The odds of improvement increased by 7% (95% CI: 6–7) per month of natalizumab treatment. The equivalent estimate was 4% (95% CI: 2–5) for other monoclonal antibodies and nonsignificant for oral or platform therapies.
Conclusion:
Treatment with natalizumab or other monoclonal antibodies is associated with a significantly faster likelihood of cognitive improvement than platform or oral DMTs.
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