549 research outputs found
Complement Activation Is Associated With Disease Severity in Multiple Sclerosis.
No full textBACKGROUND AND OBJECTIVES
Histopathologic studies have identified immunoglobulin (Ig) deposition and complement activation as contributors of CNS tissue damage in multiple sclerosis (MS). Intrathecal IgM synthesis is associated with higher MS disease activity and severity, and IgM is the strongest complement-activating immunoglobulin. In this study, we investigated whether complement components (CCs) and complement activation products (CAPs) are increased in persons with MS, especially in those with an intrathecal IgM synthesis, and whether they are associated with disease severity and progression.
METHODS
CC and CAP levels were quantified in plasma and CSF of 112 patients with clinically isolated syndrome (CIS), 127 patients with MS (90 relapsing-remitting, 14 primary progressive, and 23 secondary progressive), 31 inflammatory neurologic disease, and 44 symptomatic controls from the Basel CSF databank study. Patients with CIS/MS were followed in the Swiss MS cohort study (median 6.3 years). Levels of CC/CAP between diagnosis groups were compared; in CIS/MS, associations of CC/CAP levels with intrathecal Ig synthesis, baseline Expanded Disability Status Scale (EDSS) scores, MS Severity Score (MSSS), and neurofilament light chain (NfL) levels were investigated by linear regression, adjusted for age, sex, and albumin quotient.
RESULTS
CSF (but not plasma) levels of C3a, C4a, Ba, and Bb were increased in patients with CIS/MS, being most pronounced in those with an additional intrathecal IgM production. In CIS, doubling of C3a and C4a in CSF was associated with 0.31 (CI 0.06-0.56; p = 0.016) and 0.32 (0.02-0.62; p = 0.041) increased EDSS scores at lumbar puncture. Similarly, doubling of C3a and Ba in CIS/MS was associated with 0.61 (0.19-1.03; p < 0.01) and 0.74 (0.18-1.31; p = 0.016) increased future MSSS. In CIS/MS, CSF levels of C3a, C4a, Ba, and Bb were associated with increased CSF NfL levels, e.g., doubling of C3a was associated with an increase of 58% (Est. 1.58; CI 1.37-1.81; p < 0.0001).
DISCUSSION
CNS-compartmentalized activation of the classical and alternative pathways of complement is increased in CIS/MS and associated with the presence of an intrathecal IgM production. Increased complement activation within the CSF correlates with EDSS, future MSSS, and NfL levels, supporting the concept that complement activation contributes to MS pathology and disease progression. Complement inhibition should be explored as therapeutic target to attenuate disease severity and progression in MS
A Multicenter Longitudinal MRI Study Assessing LeMan-PV Software Accuracy in the Detection of White Matter Lesions in Multiple Sclerosis Patients.
No full textDetecting new and enlarged lesions in multiple sclerosis (MS) patients is needed to determine their disease activity. LeMan-PV is a software embedded in the scanner reconstruction system of one vendor, which automatically assesses new and enlarged white matter lesions (NELs) in the follow-up of MS patients; however, multicenter validation studies are lacking.
To assess the accuracy of LeMan-PV for the longitudinal detection NEL white-matter MS lesions in a multicenter clinical setting.
Retrospective, longitudinal.
A total of 206 patients with a definitive MS diagnosis and at least two follow-up MRI studies from five centers participating in the Swiss Multiple Sclerosis Cohort study. Mean age at first follow-up = 45.2 years (range: 36.9-52.8 years); 70 males.
Fluid attenuated inversion recovery (FLAIR) and T1-weighted magnetization prepared rapid gradient echo (T1-MPRAGE) sequences at 1.5 T and 3 T.
The study included 313 MRI pairs of datasets. Data were analyzed with LeMan-PV and compared with a manual "reference standard" provided by a neuroradiologist. A second rater (neurologist) performed the same analysis in a subset of MRI pairs to evaluate the rating-accuracy. The Sensitivity (Se), Specificity (Sp), Accuracy (Acc), F1-score, lesion-wise False-Positive-Rate (aFPR), and other measures were used to assess LeMan-PV performance for the detection of NEL at 1.5 T and 3 T. The performance was also evaluated in the subgroup of 123 MRI pairs at 3 T.
Intraclass correlation coefficient (ICC) and Cohen's kappa (CK) were used to evaluate the agreement between readers.
The interreader agreement was high for detecting new lesions (ICC = 0.97, Pvalue -20 , CK = 0.82, P value = 0) and good (ICC = 0.75, P value -12 , CK = 0.68, P value = 0) for detecting enlarged lesions. Across all centers, scanner field strengths (1.5 T, 3 T), and for NEL, LeMan-PV achieved: Acc = 61%, Se = 65%, Sp = 60%, F1-score = 0.44, aFPR = 1.31. When both follow-ups were acquired at 3 T, LeMan-PV accuracy was higher (Acc = 66%, Se = 66%, Sp = 66%, F1-score = 0.28, aFPR = 3.03).
In this multicenter study using clinical data settings acquired at 1.5 T and 3 T, and variations in MRI protocols, LeMan-PV showed similar sensitivity in detecting NEL with respect to other recent 3 T multicentric studies based on neural networks. While LeMan-PV performance is not optimal, its main advantage is that it provides automated clinical decision support integrated into the radiological-routine flow.
4 TECHNICAL EFFICACY: Stage 2
Adherence as a predictor of the development of class-specific resistance mutations: the Swiss HIV Cohort Study
No full textBACKGROUND: Non-adherence is one of the strongest predictors of therapeutic failure in HIV-positive patients. Virologic failure with subsequent emergence of resistance reduces future treatment options and long-term clinical success.
METHODS: Prospective observational cohort study including patients starting new class of antiretroviral therapy (ART) between 2003 and 2010. Participants were naïve to ART class and completed ≥1 adherence questionnaire prior to resistance testing. Outcomes were development of any IAS-USA, class-specific, or M184V mutations. Associations between adherence and resistance were estimated using logistic regression models stratified by ART class.
RESULTS: Of 314 included individuals, 162 started NNRTI and 152 a PI/r regimen. Adherence was similar between groups with 85% reporting adherence ≥95%. Number of new mutations increased with increasing non-adherence. In NNRTI group, multivariable models indicated a significant linear association in odds of developing IAS-USA (odds ratio (OR) 1.66, 95% confidence interval (CI): 1.04-2.67) or class-specific (OR 1.65, 95% CI: 1.00-2.70) mutations. Levels of drug resistance were considerably lower in PI/r group and adherence was only significantly associated with M184V mutations (OR 8.38, 95% CI: 1.26-55.70). Adherence was significantly associated with HIV RNA in PI/r but not NNRTI regimens.
CONCLUSION: Therapies containing PI/r appear more forgiving to incomplete adherence compared with NNRTI regimens, which allow higher levels of resistance, even with adherence above 95%. However, in failing PI/r regimens good adherence may prevent accumulation of further resistance mutations and therefore help to preserve future drug options. In contrast, adherence levels have little impact on NNRTI treatments once the first mutations have emerged
Serum Glial Fibrillary Acidic Protein and Neurofilament Light Chain Levels Reflect Different Mechanisms of Disease Progression under B-Cell Depleting Treatment in Multiple Sclerosis.
No full textTo investigate the longitudinal dynamics of serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) levels in people with multiple sclerosis (pwMS) under B-cell depleting therapy (BCDT) and their capacity to prognosticate future progression independent of relapse activity (PIRA) events.
A total of 362 pwMS (1,480 samples) starting BCDT in the Swiss Multiple Sclerosis (MS) Cohort were included. sGFAP levels in 2,861 control persons (4,943 samples) provided normative data to calculate adjusted Z scores.
Elevated sGFAP levels (Z score >1) at 1 year were associated with a higher hazard for PIRA (hazard ratio [HR]: 1.80 [95% CI: 1.17-2.78]; p = 0.0079) than elevated sNfL levels (HR, 1.45 [0.95-2.24], p = 0.0886) in a combined model. Independent of PIRA events, sGFAP levels longitudinally increased by 0.49 Z score units per 10 years follow-up (estimate, 0.49 [0.29, 0.69], p < 0.0001). In patients experiencing PIRA, sGFAP Z scores were 0.52 Z score units higher versus stable patients (0.52 [0.22, 0.83], p = 0.0009). Different sNfL Z score trajectories were found in pwMS with versus without PIRA (interaction p = 0.0028), with an average decrease of 0.92 Z score units per 10 years observed without PIRA (-0.92 [-1.23, -0.60], p < 0.0001), whereas levels in patients with PIRA remained high.
Elevated sGFAP and lack of drop in sNfL after BCDT start are associated with increased risk of future PIRA. These findings provide a rationale for combined monitoring of sNfL and sGFAP in pwMS starting BCDT to predict the risk of PIRA, and to use sGFAP as an outcome in clinical trials aiming to impact on MS progressive disease biology. ANN NEUROL 2024
Aberrant Complement Activation Is Associated With Structural Brain Damage in Multiple Sclerosis.
No full textLevels of activated complement proteins in the CSF are increased in people with multiple sclerosis (MS) and are associated with clinical disease severity. In this study, we determined whether complement activation profiles track with quantitative MRI metrics and liquid biomarkers indicative of disease activity and progression.
Complement components and activation products (Factor H and I, C1q, C3, C4, C5, Ba, Bb, C3a, C4a, C5a, and sC5b-9) and liquid biomarkers (neurofilament light chain, glial fibrillary acidic protein [GFAP], CXCL-13, CXCL-9, and IL-12b) were quantified in the CSF of 112 patients with clinically isolated syndromes and 127 patients with MS; longitudinal MRIs according to a standardized protocol of the Swiss MS cohort were assessed. We used multivariable models to analyze associations of the 12 complement parameters as individual independent variables and longitudinal brain volumes, T2-weighted (T2w) lesion volumes, contrast-enhancing (CELs) and paramagnetic rim lesions (PRLs), and molecular biomarkers as dependent variables, respectively.
Strongest associations with accelerated brain atrophy were found for C4a: doubling of C4a CSF levels was associated with an additional brain volume loss of -0.24% (95% CI -0.31% to -0.16%; p < 0.0001) per year, followed by Ba and C3a (-0.22% [-0.29% to -0.15%]) and -0.13% ([-0.21 to -0.06]; both p < 0.001). Doubling of C3a, Ba, and C4a levels correlated with 2.2- (1.6-3.0; p < 0.0001), 2.0- (1.3-3.1; p = 0.0038), and 1.8-fold (1.2-2.6; p = 0.0029) increased longitudinal T2w lesion volumes; C3a and Ba were associated with 2.5- (1.4-4.6; p = 0.0022) and 3.3-fold (1.5-7.2; p = 0.0024) higher odds for CELs and 2.6- (1.7-4.0; p < 0.0001) and 2.3-fold (1.3-4.3; p = 0.006) increased PRL incidence rates. C1q, C3a, and C4a were associated with higher GFAP levels, and CXCL-13, CXCL-9, and IL-12b analyses showed consistent patterns with strongest associations for C1q, followed by Ba, C3a, and C4a.
Intrathecal complement activation is consistently associated with MRI metrics and liquid biomarkers indicative for MS disease activity and progression. Our results demonstrate that aberrant complement activation is strongly associated with structural brain damage in MS. Therapeutic targeting of the complement system might limit disability accumulation due to MS
Intrathecal IgM Synthesis Is Associated with Spinal Cord Manifestation and Neuronal Injury in Early MS
No full textOBJECTIVE
Intrathecal Immunoglobulin M synthesis (IgMIntrathecal Fraction (IF) + ) and spinal MRI lesions are both strong independent predictors of higher disease activity and severity in multiple sclerosis (MS). We investigated whether IgMIF + is associated with spinal cord manifestation and higher neuroaxonal damage in early MS.
METHODS
In 122 patients with a first demyelinating event associations between 1.) spinal versus (vs) non-spinal clinical syndrome 2.) spinal vs cerebral T2-weighted (T2w) and 3.) contrast-enhancing (CE) lesion counts with IgGIF + (vs IgGIF - ) or IgMIF + (vs IgMIF - ) were investigated by logistic regression adjusted for age and sex, respectively. For serum neurofilament light chain (sNfL) analysis patients were categorized for presence or absence of oligoclonal IgG bands (OCGB), IgGIF and IgMIF (>0% vs 0%, respectively): 1) OCGB- /IgGIF - /IgMIF - ; 2) OCGB+ /IgGIF - /IgMIF - ; 3) OCGB+ /IgGIF + /IgMIF - ; and 4) OCGB+ /IgGIF + /IgMIF + . Associations between categories 2) to 4) vs category 1 with sNfL concentrations were analyzed by robust linear regression, adjusted for sex and MRI parameters.
RESULTS
Patients with a spinal syndrome had a 8.36-fold higher odds of IgMIF + (95%CI 3.03-23.03; p <0.01). Each spinal T2w lesion (odds Ratio 1.39; 1.02-1.90; p = 0.037) and CE lesion (OR 2.73; 1.22-6.09; p = 0.014) was associated with an increased risk of IgMIF + (but not of IgGIF + ); this was not the case for cerebral lesions. OCGB+ /IgGIF + /IgMIF + category patients showed highest sNfL levels (estimate:1.80; 0.55-3.06; p <0.01).
INTERPRETATION
Intrathecal IgM synthesis is strongly associated with spinal manifestation and independently more pronounced neuroaxonal injury in early MS, suggesting a distinct clinical phenotype and pathophysiology. This article is protected by copyright. All rights reserved
Treatment Strategies and Disease Activity During Pregnancy and Postpartum: Real-World Data From the Swiss Multiple Sclerosis Cohort.
No full textManaging multiple sclerosis (MS) during pregnancy and postpartum is a therapeutic challenge. We aim to describe therapy regimens, clinical and MRI disease activity, and serum neurofilament light chain (sNfL) levels in all pregnancies observed between 2012 and 2023 among participants of the Swiss MS cohort.
We assessed the treatment strategies during pregnancy and 1 year postpartum in all included pregnancies. We compared pregnancies continuously exposed to high-efficacy disease-modifying therapies (cHET: anti-CD20 monoclonal antibodies (aCD20) and natalizumab [NTZ]) with those where other therapeutic regimens (OTRs) were used. Disease activity was assessed by occurrence of relapses or new or enlarging T2w lesions (neT2Ls), as well as sNfL Z scores. We estimated odds ratios adjusted for age, disease duration, Expanded Disability Status Scale (EDSS) score, and previous relapse rate using generalized estimating equation (GEE) models for the relapse endpoint and using Firth logistic regression for MRI activity. sNfL Z scores were compared between treatment categories at sampling using GEE models.
We analyzed 123 pregnancies in 93 women (median age [interquartile range {IQR}] 32.2 years [29.3, 35.7]; EDSS score [IQR] 1.5 [1.0, 2.0]). The last disease-modifying therapy (DMT) before birth was NTZ in 29 (23.5%) and aCD20 in 25 (20.3%) pregnancies; of those, 3 and 24 were exposed until birth, respectively (cHET). Fingolimod was the last treatment before birth in 25 pregnancies (20.3%), stopped in all before or after confirmation of pregnancy. Other DMTs were used in 39 pregnancies (31.7%); 5 remained untreated. Compared with cHET, patients with pregnancies under OTRs had higher proportions of relapses (34.4% vs 13.0%; n = 113, OR 4.52, 95% CI [1.35-15.11], p = 0.0142) and neT2Ls (40.9% vs 3.8%; n = 91, OR 9.15, 95% CI [2.14-85.21], p = 0.0013). sNfL Z scores during pregnancy and postpartum were higher in patients untreated at sampling compared with patients under high-efficacy DMT (HET) (+0.43 Z score units, 95% CI [0.05-0.81], p = 0.0255). No serious adverse events were observed.
Treatment strategies for pregnant patients with MS were heterogeneous, and continuous exposure to HET showed superior efficacy against acute disease activity compared with other DMTs or no treatment. Further studies are needed to confirm these results and assess maternal and fetal longer term outcomes
Comparative effectiveness of teriflunomide and ocrelizumab on smoldering activity in multiple sclerosis: an observational study in the Swiss Multiple Sclerosis Cohort.
No full textThis study aimed to compare the effects of teriflunomide and ocrelizumab on clinical and MRI endpoints related to smoldering activity in relapsing-remitting multiple sclerosis (RRMS).
In this observational, longitudinal, multicenter study, we included 128 people with RRMS (pwRRMS) treated with teriflunomide and 495 treated with ocrelizumab. Outcomes included time to progression independent of relapse activity (PIRA). In a subset, we also assessed brain volume loss (BVL), longitudinal changes in diffusion tensor imaging (DTI) metrics, and the burden of paramagnetic rim lesions (PRLs). Propensity score matching was used for between-group comparisons.
Over a median follow-up of 3.1 years in the ocrelizumab group and 1.9 years in the teriflunomide group, there were no significant differences in the risk of PIRA (HR for teriflunomide vs. ocrelizumab: 0.80 [95%-CI:0.40-1.60]; p = 0.53). PwRRMS treated with teriflunomide exhibited lower annualized rates of BVL (-0.80 [95%-CI: -0.91; -0.69] vs. -1.06 [95%-CI: -1.25; -0.86]; p = 0.025) and gray matter volume loss (-0.92 [95%-CI: -1.05; -0.79] vs. -1.20 [95%-CI: -1.43; -0.97]; p = 0.035). No differences were observed in DTI metrics or PRL count.
This real-world study suggests that teriflunomide shows similar efficacy to ocrelizumab on smoldering activity, with a potentially greater effect in reducing BVL. Further research is needed to confirm these findings and understand their long-term implications
Resurgence of HIV infection among men who have sex with men in Switzerland : mathematical modelling study
No full textNew HIV infections in men who have sex with men (MSM) have increased in Switzerland since 2000 despite combination antiretroviral therapy (cART). The objectives of this mathematical modelling study were: to describe the dynamics of the HIV epidemic in MSM in Switzerland using national data; to explore the effects of hypothetical prevention scenarios; and to conduct a multivariate sensitivity analysis. METHODOLOGY/PRINCIPAL FINDINGS: The model describes HIV transmission, progression and the effects of cART using differential equations. The model was fitted to Swiss HIV and AIDS surveillance data and twelve unknown parameters were estimated. Predicted numbers of diagnosed HIV infections and AIDS cases fitted the observed data well. By the end of 2010, an estimated 13.5% (95% CI 12.5, 14.6%) of all HIV-infected MSM were undiagnosed and accounted for 81.8% (95% CI 81.1, 82.4%) of new HIV infections. The transmission rate was at its lowest from 1995-1999, with a nadir of 46 incident HIV infections in 1999, but increased from 2000. The estimated number of new infections continued to increase to more than 250 in 2010, although the reproduction number was still below the epidemic threshold. Prevention scenarios included temporary reductions in risk behaviour, annual test and treat, and reduction in risk behaviour to levels observed earlier in the epidemic. These led to predicted reductions in new infections from 2 to 26% by 2020. Parameters related to disease progression and relative infectiousness at different HIV stages had the greatest influence on estimates of the net transmission rate. CONCLUSIONS/SIGNIFICANCE: The model outputs suggest that the increase in HIV transmission amongst MSM in Switzerland is the result of continuing risky sexual behaviour, particularly by those unaware of their infection status. Long term reductions in the incidence of HIV infection in MSM in Switzerland will require increased and sustained uptake of effective interventions
Symptoms in Swiss adolescents in relation to exposure from fixed site transmitters : a prospective cohort study
No full textThere is public concern regarding potential health effects of radiofrequency electromagnetic fields (RF-EMF) emitted by fixed site transmitters. We therefore investigated whether self-reported general well-being in adolescents is affected by RF-EMF exposure from mobile phone base stations (downlink) and broadcast transmitters (TV and radio).; In a prospective cohort study, 439 study participants aged 12-17 years, completed questionnaires about their self-reported well-being and possible confounding factors at baseline and one year later. Exposure from fixed site transmitters at home and school was calculated by using a geospatial propagation model. Data were analysed using a mixed-logistic cross-sectional model of a combined dataset consisting of baseline and follow-up data and a longitudinal approach where we investigated whether exposure at baseline (cohort analysis) or changes in exposure between baseline and follow-up (change analysis) were related to a new onset of a symptom between baseline and follow-up. All analyses were adjusted for relevant confounders.; Mean exposure (median; 75(th)) for broadcast transmitters, downlink and total exposure at baseline were 1.9 μW/m(2) (1.0 μW/m(2); 2.8 μW/m(2)), 14.4 μW/m(2) (3.8 μW/m(2); 11.0 μW/m(2)) and 16.3 μW/m(2) (5.8 μW/m(2); 13.4 μW/m(2)), respectively. In cross-sectional analyses no associations were observed between any symptom and RF-EMF exposure from fixed site transmitters. In the cohort and change analyses only a few significant associations were observed including an increased OR for tiredness (2.94, 95%CI: 1.43 to 6.05) for participants in the top 25(th) percentile of total RF-EMF exposure from fixed site transmitters at baseline, in comparison to participants exposed below the median and a decreased OR for exhaustibility (0.50, 95%CI: 0.27 to 0.93) for participants with an exposure increase between baseline and follow-up.; In this cohort study, using a geospatial propagation model, RF-EMF exposure from fixed site transmitters was not consistently associated with self-reported symptoms in Swiss adolescents. The few observed associations have to be interpreted with caution and might represent chance findings
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