Neurofilaments are structural proteins, and neurofilament light chain (NfL) is released after neuroaxonal injury.1 NfL can be measured in blood by ultrasensitive assays, with good correlation between ...blood and CSF levels.1,2 In healthy individuals, blood concentrations of NfL increase with age. ...it should be noted that NfL concentrations measured with methods other than the one used in this study might not provide valid Z scores for the app. ...NfL concentrations in plasma tend to be lower than those in serum5,8 and, therefore, might also not be valid with the app. ...the use of NfL Z scores to estimate risk of progression independent of relapses and MRI activity in multiple sclerosis remains to be established.10 FS declares grants from Biogen, Merck, Novartis, Roche, and Sanofi Genzyme; consulting fees from Novartis; speaking fees from Biogen, Bristol Myers Squibb, Merck, Novartis, Roche, and Sanofi Genzyme; travel support from Biogen and Roche; and fees for participating on a Data Safety Monitoring Board from Alexion, Biogen, Bristol Myers Squibb, Merck, Novartis, Roche, and Sanofi Genzyme.
Whereas drugs used for maintenance/escalation therapy do not maintain their beneficial effect after cessation of therapy, some new highly effective therapies can show prolonged treatment effects ...after a short treatment course. Such therapies have been named pulsed immune reconstitution therapies or pulsed immunosuppressive therapies, and typical representatives are alemtuzumab and cladribine. Autologous haematopoietic stem cell transplantation could be considered as the strongest immune reconstitution therapy. Both alemtuzumab and cladribine induce depletion of lymphocytes, and a common mechanism of action is preferential depletion of class-switched and unswitched memory B-cells. Whereas CD-19+ B-lymphocytes repopulate within 6 months, CD4+ T-cells repopulate at a slower rate, taking 1–2 years to reach the lower level of normal. In general, the depletion of lymphocytes is more profound and the repletion of T-cells is slower after alemtuzumab than after cladribine treatment. Both drugs have a strong effect on relapses and magnetic resonance imaging (MRI) activity, and reduce disability worsening. The therapeutic effect is maintained beyond the period of active treatment in a large proportion of patients, which is best documented for alemtuzumab. Adverse effects include reactivation of latent infections such as tuberculosis and risk of herpes zoster. The main disadvantage in alemtuzumab-treated patients is the risk of secondary immune-mediated disorders. Pulsed immune reconstitution therapy is an option as initial therapy in relapsing-remitting multiple sclerosis patients with high disease activity and in patients on treatment with another disease-modifying therapy with significant relapse and/or MRI activity.
Background and purpose
Data on pregnancy outcomes following fetal exposure to disease‐modifying drugs (DMDs) in women with multiple sclerosis (MS) are sparse although growing.
Methods
Data from the ...Danish Multiple Sclerosis Registry were linked with nationwide registries enabling an investigation of adverse pregnancy outcomes in newborns of women with MS following fetal exposure to injectable first‐line treatments, dimethyl fumarate, glatiramer acetate, or natalizumab. Logistic regression models accounting for clustered data were used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for individual and composite adverse outcomes after adjusting for relevant covariates.
Results
A total of 1009 DMD‐exposed pregnancies were compared with 1073 DMD‐unexposed pregnancies as well as 91,112 pregnancies from the general population. No association of an increased risk of any perinatal outcome was found when comparing newborns with fetal exposure with the general population, including preterm birth (OR = 1.19, 95% CI = 0.86–1.64), small for gestational age (OR = 1.38, 95% CI = 0.92–2.07), spontaneous abortion (OR = 1.04, 95% CI = 0.84–1.27), congenital malformation (OR = 0.99, 95% CI = 0.68–1.45), low Apgar score (OR = 0.62, 95% CI = 0.23–1.65), stillbirth (OR = 1.05, 95% CI = 0.33–3.31), placenta complication (OR = 0.53, 95% CI = 0.22–1.27), and any adverse event (OR = 1.10, 95% CI = 0.93–1.30). Similar results were found when comparing DMD‐exposed pregnancies with DMD‐unexposed pregnancies.
Conclusions
We found no increased association of adverse pregnancy outcomes in newborns with fetal exposure to DMDs when compared with either DMD‐unexposed pregnancies or the general population.
A number of studies have reported flare-up of multiple sclerosis (MS) disease activity after cessation of natalizumab, increasing to a level beyond the pre-natalizumab treatment level. Our aim was to ...describe the development in clinical disease activity following cessation of natalizumab therapy in a large unselected cohort of highly active patients. We studied 375 highly active patients who had suffered at least two significant relapses within 1 year or three relapses within 2 years, or had been treated with mitoxantrone for highly active disease. All patients had discontinued therapy with natalizumab after at least 24 weeks on therapy, and had been followed 3–12 months (mean 8.9 months) after cessation of natalizumab therapy. The annualised relapse rate before start of natalizumab therapy was 0.94 (95 % confidence interval CI 0.88–1.00), 0.47 (95 % CI 0.43–0.52) during natalizumab therapy, 0.63 (95 % CI 0.51–0.76) 1–6 months after natalizumab and 0.55 (95 % CI 0.42–0.70) 7–12 months after natalizumab. However, 83 (22 %) of the patients could be classified as showing rebound of relapses, defined as a higher individual relapse rate after cessation of natalizumab than before natalizumab. These patients had a higher annualised relapse rate during natalizumab therapy. For the whole patient group, the relapse rate after discontinuation did not exceed the pre-natalizumab relapse rate at any time, but 22 % of the patients showed rebound of relapses after discontinuation of natalizumab.
Background:
Fingolimod may be associated with risk of developing cardiovascular disease (CVD). Studies including reference groups and long follow-up are scarce.
Objectives:
We hypothesized that ...patients treated with fingolimod would be at higher risk of developing CVD compared to patients treated with natalizumab.
Methods:
A nationwide 12-year cohort study linking individual-level data from the Danish Multiple Sclerosis Registry with health registries on 2095 adult patients with multiple sclerosis (MS) without any health records of CVD at follow-up start. Exposure to fingolimod and natalizumab was defined by the first treatment of at least 3 months. Cohort entry was from 2011 to 2018. We defined CVD as a composite measure, including hypertension, ischemic heart disease, atrial fibrillation, heart failure, and stroke. We used multivariable adjusted Cox regression.
Results:
There were 28.8 and 17.4 CVD events per 1000 person-years in fingolimod and natalizumab groups, respectively. Compared to natalizumab-treated patients, fingolimod-treated patients had a higher risk of CVD (hazard ratio (HR) = 1.57; 95% confidence interval (CI) = 1.18–2.08). Hypertension comprised 200 of 244 CVD events.
Conclusion:
We found an increased risk of CVD in patients with MS treated with fingolimod. This increased risk was mainly due to hypertension.
Pathology studies of progressive multiple sclerosis (MS) indicate a major role of inflammation including Th17-cells and meningeal inflammation with ectopic lymphoid follicles, B-cells and plasma ...cells, the latter indicating a possible role of the newly identified subset of follicular T-helper (TFH) cells. Although previous studies reported increased systemic inflammation in progressive MS it remains unclear whether systemic inflammation contributes to disease progression and intrathecal inflammation. This study aimed to investigate systemic inflammation in progressive MS and its relationship with disease progression, using flow cytometry and gene expression analysis of CD4(+) and CD8(+)T-cells, B-cells, monocytes and dendritic cells. Furthermore, gene expression of cerebrospinal fluid cells was studied. Flow cytometry studies revealed increased frequencies of ICOS(+)TFH-cells in peripheral blood from relapsing-remitting (RRMS) and secondary progressive (SPMS) MS patients. All MS subtypes had decreased frequencies of Th1 TFH-cells, while primary progressive (PPMS) MS patients had increased frequency of Th17 TFH-cells. The Th17-subset, interleukin-23-receptor(+)CD4(+)T-cells, was significantly increased in PPMS and SPMS. In the analysis of B-cells, we found a significant increase of plasmablasts and DC-SIGN(+) and CD83(+)B-cells in SPMS. ICOS(+)TFH-cells and DC-SIGN(+)B-cells correlated with disease progression in SPMS patients. Gene expression analysis of peripheral blood cell subsets substantiated the flow cytometry findings by demonstrating increased expression of IL21, IL21R and ICOS in CD4(+)T-cells in progressive MS. Cerebrospinal fluid cells from RRMS and progressive MS (pooled SPMS and PPMS patients) had increased expression of TFH-cell and plasmablast markers. In conclusion, this study is the first to demonstrate the potential involvement of activated TFH-cells in MS. The increased frequencies of Th17-cells, activated TFH- and B-cells parallel findings from pathology studies which, along with the correlation between activated TFH- and B-cells and disease progression, suggest a pathogenic role of systemic inflammation in progressive MS. These observations may have implications for the treatment of progressive MS.
Over the past two decades, treatment options for patients with multiple sclerosis (MS) have increased exponentially. In the current therapeutic landscape, “no evidence of MS disease activity” is ...within reach in many of our patients. Minimizing risks of complications, improving treatment convenience, and decreasing health care costs are goals that are yet to be reached. One way to optimize MS therapy is to implement personalized or extended interval dosing. Monoclonal antibodies are suitable candidates for personalized dosing (by therapeutic drug monitoring) or extended interval dosing. An increasing number of studies are performed and underway reporting on altered dosing intervals of anti-α4β1-integrin treatment (natalizumab) and anti-CD20 treatment (ocrelizumab, rituximab, and ofatumumab) in MS. In this review, current available evidence regarding personalized and extended interval dosing of monoclonal antibodies in MS is discussed with recommendations for future research and clinical practice.
Background:
Neurofilament light chain (NFL) and chitinase-3-like-1 (CHI3L1) concentrations in cerebrospinal fluid (CSF) may have prognostic value in clinically isolated syndromes (CIS) and ...relapsing–remitting multiple sclerosis (RRMS).
Objectives:
To compare the prognostic value of CSF concentrations of NFL and CHI3L1 in newly diagnosed CIS and RRMS patients.
Methods:
NFL and CHI3L1 were measured in CSF in 177 newly diagnosed patients with CIS or RRMS who were followed clinically for a mean of 5.7 years.
Results:
At baseline CSF concentrations of NFL correlated with CSF concentrations of CHI3L1, relapses in the previous year, time from last relapse, and the Expanded Disability Status Scale (EDSS) score. CSF concentrations of NFL and CHI3L1 were both associated with increased relapse risk during the first 2 years in univariate analyses, but only the CSF concentration of NFL was independently associated with relapse risk in a multivariable analysis. There was no relationship between CSF concentrations of NFL or CHI3L1 and risk of conversion to secondary progressive MS or development of disability.
Conclusion:
CSF concentrations of NFL are associated with 2-year relapse risk but not with disease progression or clinical worsening in newly diagnosed CIS and RRMS patients. This may be due to confounding by the effect of disease-modifying therapies.
Multiple sclerosis (MS) is a chronic disease with an inflammatory and neurodegenerative pathology. Axonal loss and neurodegeneration occurs early in the disease course and may lead to irreversible ...neurological impairment. Changes in brain volume, observed from the earliest stage of MS and proceeding throughout the disease course, may be an accurate measure of neurodegeneration and tissue damage. There are a number of magnetic resonance imaging-based methods for determining global or regional brain volume, including cross-sectional (e.g. brain parenchymal fraction) and longitudinal techniques (e.g. SIENA Structural Image Evaluation using Normalization of Atrophy). Although these methods are sensitive and reproducible, caution must be exercised when interpreting brain volume data, as numerous factors (e.g. pseudoatrophy) may have a confounding effect on measurements, especially in a disease with complex pathological substrates such as MS. Brain volume loss has been correlated with disability progression and cognitive impairment in MS, with the loss of grey matter volume more closely correlated with clinical measures than loss of white matter volume. Preventing brain volume loss may therefore have important clinical implications affecting treatment decisions, with several clinical trials now demonstrating an effect of disease-modifying treatments (DMTs) on reducing brain volume loss. In clinical practice, it may therefore be important to consider the potential impact of a therapy on reducing the rate of brain volume loss. This article reviews the measurement of brain volume in clinical trials and practice, the effect of DMTs on brain volume change across trials and the clinical relevance of brain volume loss in MS.
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