EDSS Change Research Articles

Efficacy and safety of apheresis therapy in AQP4 antibody-positive NMOSD attack: A propensity score-matched cohort study.

Plasma exchange (PE) and immunoadsorption (IA) are recognized as effective ways to treat attacks in AQP4 antibody-positive NMOSD, but high-quality evidence was lacking. To evaluate the efficacy and safety of PE/IA plus intravenous methylprednisolone (IVMP) in NMOSD attacks using propensity scores to match IVMP as control. Patients were from a prospective observational cohort study. Stratification and interval propensity score matching (PSM) were used to reduce selection bias by matching baseline characteristics (gender, age, time to IVMP, EDSS at attack) between PE/IA + IVMP and IVMP group (in a ratio of 1:2). The primary endpoint of efficacy was EDSS change at 6 months. Adverse events and changes in laboratory tests were recorded. Four hundred and eleven attacks of 336 patients were screened for PSM, and 90 attacks (30 PE/IA + IVMP and 60 IVMP) were included in the analysis. There were significant differences in EDSS [6.25 vs. 6.75; IQR (4.50-8.38 vs. 5.00-8.00), p = 0.671] and visual acuity [median logMAR = 0.35 vs. 1.00; IQR (0.30-0.84 vs. 0.95-1.96), p = 0.002] change between two groups at 6 months. PE/IA + IVMP treatment demonstrated predictive capacity for good recovery as indicated by an area under the curve (AUC) of 0.726. Fibrinogen reduction was found during PE/IA + IVMP treatment [n = 15 (50.00%)], but no severe adverse events led to apheresis treatment discontinuation. After PSM analysis, IVMP+PE/IA in acute attack of NMOSD achieved better and continuous improvement in neurological function within 6 months compared with IVMP alone. PE/IA treatment showed a good safety profile.

Progression independent of relapses in aquaporin4-IgG-seropositive neuromyelitis optica spectrum disorder, myelin oligodendrocyte glycoprotein antibody-associated disease, and multiple sclerosis

ObjectivesTo determine whether progression independent of relapse activity (PIRA) is present in Aquaporin4-IgG-seropositive neuromyelitis optica spectrum disorder (AQP4+NMOSD), Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and relapsing remitting Multiple sclerosis (RRMS). MethodsWe retrospectively studied the change in EDSS, confirmed disability worsening (CDW) (i.e., PIRA), and new MRI lesions in AQP4+NMOSD, and MOGAD and MS patients. Linear mixed-effect regression model was used to compare the longitudinal changes in EDSS, and Cox regression was used to compare changes in MRI. ResultsThe estimated mean ΔEDSS in the AQP4+NMOSD and matched MS group were +0.06 (95%CI: -0.40, +0.52, p = 0.76), and +0.02 (95%CI: -0.05, +0.08, p = 0.6) respectively. The same estimate was -0.08 (95%CI: -0.18, +0.02, p = 0.12) in MOGAD and +0.05 (95%CI: -0.05, +0.15, p = 0.35) in matched MS group. Comparing groups for the presence of CDW (i.e., PIRA) showed that PIRA is more associated with MS compared to AQP4+NMOSD (p = 0.02) and MOGAD (p<0.001). Compared to their matched MS groups, the annualized rate of PIRA was significantly lower in AQP4 (0.08 vs 0.44; p<0.0001), and MOG groups (0.04 vs 0.13; p<0.0001). New T2 or enhancing lesions on brain MRI were higher in MS compared to AQP4+NMOSD and MOGAD patients. ConclusionRelapse-independent changes in the EDSS, CDW, and MRI activity are not common in AQP4+NMOSD and MOGAD, especially when compared with MS. Since our patients were on relapse prevention therapies at the time of EDSS measurements, our study supports the importance of preventing relapses in AQP4+NMOSD and MOGAD and suggests different pathologic mechanisms of relapse-free neurological damage between MS and AQP4+NMOSD/MOGAD.

Disability progression and worse cognitive status are associated with higher concurrent brain atrophy rates (P13-3.007)

<h3>Objective:</h3> To determine associations between brain atrophy rate and clinical outcome measures in multiple sclerosis (MS). <h3>Background:</h3> The determination and treatment of neurodegenerative aspects of MS remains a challenge. One indirect form of assessment is the whole brain atrophy rate as determined by longitudinal MRI. Integration of brain atrophy rate assessments into clinical practice is hampered by multiple technical and translational factors, including incomplete clinical validation. It remains unclear to what extent clinical assessments are reflected and associated with this measure. <h3>Design/Methods:</h3> In a large retrospective observational cohort, we used FSL-SIENA to determine annualized percent brain volume change (aPBVC) from longitudinal clinical 3T MRI obtained using a uniform hardware and software acquisition protocol. Clinical outcomes, including confirmed disability progression, the 9-hole peg test (9HPT), the symbol digit modalities test (SDMT), and the timed-25-foot walk (T25w) were determined from retrospective chart review. SDMT, 9HPT, and T25w were averaged between the first and second MRI sessions to produce a single number. Using forward regression models, we assessed clinical predictors of aPBVC, including CDP and secondary clinical outcome measures, as independent variables along with age of onset and type of MS. <h3>Results:</h3> 123 patients met inclusion criteria (102 RMS, 21 PMS; mean age = 36 ±SD 11) with available clinical and MRI data. In univariable analyses, confirmed disability progression showed the strongest association with concurrent aPBVC (β=0.31, p &lt;0.001), followed by the SDMT (β=0.27, p=0.006) whereas 9HPT and T25 were not significant (p&gt;0.05). Change in EDSS and cross-sectional SDMT both remained significantly associated in multivariable models (p=0.008 and p=0.04, respectively). <h3>Conclusions:</h3> Both disability progression as well as the SDMT are independently associated with the observed brain atrophy rate. <b>Disclosure:</b> Dr. Garcia-Dominguez has nothing to disclose. Dr. Hemond has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for VIVIO Health. Dr. Hemond has stock in VIVIO Health. The institution of Dr. Hemond has received research support from Consorium of Multiple Sclerosis Centers. The institution of Dr. Hemond has received research support from National Multiple Sclerosis Society. The institution of Dr. Hemond has received research support from National Center for Advancing Translational Sciences, National Institutes of Health. The institution of Dr. Hemond has received research support from University of Massachusetts Memorial Medical Center. The institution of Dr. Hemond has received research support from National Institute Of Neurological Disorders And Stroke of the National Institutes of Health. Dr. Hemond has received personal compensation in the range of $0-$499 for serving as a Member of Data Safety and Monitoring Board with National Institute Of Neurological Disorders And Stroke of the National Institutes of Health.

Serum and cerebrospinal fluid BDNF concentrations are associated with neurological and cognitive improvement in multiple sclerosis: A pilot study.

Biomarkers of disease activity have been intensively studied in multiple sclerosis (MS) but knowledge on predictors of disability improvement is limited. The aim of this pilot study was to explore whether increased brain-derived neurotrophic factor concentrations in serum and CSF (sBDNF/cBDNF) precede neurological and cognitive improvement in MS. In this pilot, monocentric prospective cohort study we collected serum/CSF samples at baseline together with EDSS (n=36) and cognitive testing (n=34) in patients with relapsing-remitting/primary progressive MS or clinically isolated syndrome. BDNF was assessed in serum and CSF with a single molecule array (SIMOA) HD-1 analyser (Quanterix). Twelve months later EDSS and cognitive testing were repeated. BDNF concentrations of patients with vs. without disability or cognitive improvement (disability improvement: decrease in EDSS ≥ 0.5; cognitive improvement: average z-score increase in neuropsychological performance ≥ 0.5) were compared using univariate ANOVAs adjusting for covariates. Compared to subjects without, patients with disability improvement had higher sBDNF at baseline (q=0.04). Subjects with cognitive improvement had higher cBDNF at baseline than those without cognitive improvement (q=0.004). Secondary analysis demonstrated significant correlations between sBDNF and EDSS change (q=0.036), cBDNF and average z-score change (q=0.04) and cBDNF and number of cognitive tests with improvement (q=0.04), while controlling for covariates. Our findings suggest a possible role for BDNF in neurological and cognitive improvement in MS. These findings have to be confirmed in a larger sample but they already highlight the potential of BDNF as a biomarker for disability improvement and neuroplasticity in MS.

CSF lymphocytic pleocytosis does not predict a less favourable long-term prognosis in MS

ObjectiveThe role of CSF lymphocytic pleocytosis in predicting the clinical outcome of multiple sclerosis is unclear. We explored the impact of CSF pleocytosis at diagnosis on long-term disease progression in a large UK cohort.MethodsWe extracted demographic, clinical and CSF data of people with MS attending the MS clinics between 1996 and 2014 at two MS centres from the English Midlands. We compared EDSS at onset, follow up EDSS and progression indices Multiple Sclerosis Severity Score (MSSS), annualized change in EDSS and transition to secondary progression in the presence/absence of pleocytosis. Two-tailed student t-test, Mann–Whitney U test, Chi-Square or Fisher’s exact tests were used for detecting the differences.ResultsA total of 247 patients with MS (178 females; mean age 42.4; 217 with relapsing onset) were followed up for an average of 13.56 years (median 12 years). Almost 18% had lymphocytic CSF ≥ 5 per microliter. CSF pleocytosis was not associated with higher EDSS at the time of LP or at follow up, and other progression indices like MSSS, annualized change in EDSS or transition to secondary progression.DiscussionCSF pleocytosis at MS diagnosis does not predict higher long-term disability and has no long-term prognostic value in routine clinical circumstances. Differences between MS populations and potential differences in disease activity at the time of CSF analysis may account for differences between studies.

Fitts' Tapping Task as a New Test for Cognition and Manual Dexterity in Multiple Sclerosis: Validation Study.

Introduction. Studies suggest that people with multiple sclerosis (pwMS) experience continuous and subclinical physical worsening, even as early as their disease diagnosis. Validating sensitive and reproducible tests that can capture subclinical disease activity early in the disease are clinically useful and highly warranted. We aimed at validating the utility of Fitts’ Tapping Task (FTT) as reproducible measure of psychomotor performance in pwMS. Materials and Methods. Thirty newly-diagnosed pwMS (within 2 years of diagnosis and Expanded Disability Status Scale; EDSS ≤ 2.0), 30 people with migraine (pwMig), and 30 healthy controls (HCs) underwent a psychomotor assessment using the FTT, O’Connor hand dexterity test, and Visual Reaction Time Test (VRTT). Hand strength was measured using a hand-grip dynamometer. Subjects also provided patient-reported outcomes (PROs) using the 36-Item Short Form Survey (SF-36). Intrarater and interrater reproducibility was acquired on 5 HCs by two independent operators. Test−retest reproducibility was determined in 5 pwMS over a 1-week follow-up. Eight pwMS returned for the same test procedures 2 years after the baseline assessment. Bland−Altman plots were used to determine the minimally detectable change (MDC) and logistic regression models determined the ability to differentiate between newly-diagnosed pwMS and HCs. Results. FTT exhibited a high intrarater and interrater reproducibility (interclass correlation coefficient of 0.961, p < 0.001). The test−retest demonstrated an MDC of the average FTT at > 15%. PwMS had significantly a slower FTT time and O’Connor dexterity time when compared to pwMig and HCs (p < 0.001 for both). Higher Fitts’ difficulty levels (4th and 6th difficulty) and average performance on the O’Connor test were able to differentiate newly-diagnosed pwMS from HCs with 80% accuracy (p < 0.01). Slower FTT performance was correlated with worse PROs due to physical health. Over the 2-year follow-up, and despite being clinically stable (no change in EDSS), 6 out of 8 (75%) pwMS had more than a 15% worsening in their average FTT time. Conclusions. FTT is a highly-reproducible test for measuring psychomotor performance in newly-diagnosed pwMS. FTT can capture insidious worsening in psychomotor performance and cognitive function in early stages of MS.

HLA-DRB1*1501 influences long-term disability progression and tissue damage on MRI in relapse-onset multiple sclerosis

Background: Whether genetic factors influence the long-term course of multiple sclerosis (MS) is unresolved. Objective: To determine the influence of HLA-DRB1*1501 on long-term disease course in a homogeneous cohort of clinically isolated syndrome (CIS) patients. Methods: One hundred seven patients underwent clinical and MRI assessment at the time of CIS and after 1, 3, 5 and 15 years. HLA-DRB1*1501 status was determined using Sanger sequencing and tagging of the rs3135388 polymorphism. Linear/Poisson mixed-effects models were used to investigate rates of change in EDSS and MRI measures based on HLA-DRB1*1501 status. Results: HLA-DRB1*1501 -positive (n = 52) patients showed a faster rate of disability worsening compared with the HLA-DRB1*1501 -negative (n = 55) patients (annualised change in EDSS 0.14/year vs. 0.08/year, p < 0.025), and a greater annualised change in T2 lesion volume (adjusted difference 0.45 mL/year, p < 0.025), a higher number of gadolinium-enhancing lesions, and a faster rate of brain (adjusted difference −0.12%/year, p < 0.05) and spinal cord atrophy (adjusted difference −0.22 mm2/year, p < 0.05). Interpretation: These findings provide evidence that the HLA-DRB1*1501 allele plays a role in MS severity, as measured by long-term disability worsening and a greater extent of inflammatory disease activity and tissue loss. HLA-DRB1*1501 may provide useful information when considering prognosis and treatment decisions in early relapse-onset MS.

Two years’ effect of dimethyl fumarate on focal and diffuse gray matter pathology in multiple sclerosis

Background: Data on the effect of dimethyl fumarate (DMF) on focal and diffuse gray matter (GM) damage, a relevant pathological substrate of multiple sclerosis (MS)-related disability are lacking. Objective: To evaluate the DMF effect on cortical lesions (CLs) accumulation and global and regional GM atrophy in subjects with relapsing–remitting MS. Methods: A total of 148 patients (mean age 38.1 ± 9.7 years) treated with DMF ended a 2-year longitudinal study. All underwent regular Expanded Disability Status Scale (EDSS assessment), and at least two 3T-magnetic resonance imaging (MRI) at 3 and 24 months after DMF initiation. CLs and changes in global and regional atrophy of several brain regions were compared with 47 untreated age and sex-matched patients. Results: DMF-treated patients showed lower CLs accumulation (median 0[0–3] vs 2[0–7], p < 0.001) with respect to controls. Global cortical thickness (p < 0.001) and regional thickness and volume were lower in treated group (cerebellum, hippocampus, caudate, and putamen: p < 0.001; thalamus p = 0.03). Lower relapse rate (14% vs 40%, p < 0.001), EDSS change (0.2 ± 0.4 vs 0.4 ± 0.9, p < 0.001), and new WM lesions (median 0[0–5] vs 2[0–6], p < 0.001) were reported. No severe adverse drug reactions occurred. Conclusions: Beyond the well-known effect on disease activity, these results provide evidence of the effect of DMF through reduced progression of focal and diffuse GM damage.

Prognostic Markers of Ocrelizumab Effectiveness in Multiple Sclerosis: A Real World Observational Multicenter Study.

Pivotal trials showed the effectiveness of the monoclonal antibody ocrelizumab in relapsing and progressive multiple sclerosis (MS). However, data on everyday practice in MS patients and markers of treatment effectiveness are scarce. We aimed to collect real-world data from ocrelizumab-treated MS patients, relapsing-remitting (RR) and progressive MS patients (PMS), including active secondary progressive MS (aSPMS) and primary progressive MS (PPMS) patients, and to explore potential prognostic factors of clinical outcome. Patients were enrolled at MS centres in the Campania region, Italy. We collected clinic-demographic features retrospectively one year before ocrelizumab start (T−1), at ocrelizumab start (T0), and after one year from ocrelizumab start (T1). We explored possible clinical markers of treatment effectiveness in those patients receiving ocrelizumab treatment for at least one year using multilevel-mixed models. We included a total of 383 MS patients (89 RRMS and 294 PMS; 205 females, mean age: 45.8 ± 11.2, disease duration: 12.7 ± 11.6 years). Patients had a mean follow-up of 12.4 ± 8.2 months, and 217 patients completed one-year ocrelizumab treatment. Overall, EDSS increased from T−1 to T0 (coeff. = 0.30, 95% coefficient interval [CI] = 0.19–0.41, p < 0.001) without a further change between T0 and T1 (p = 0.61). RRMS patients did not show an EDSS change between T−1 and T0 nor between T0 and T1. Conversely, PMS patients showed EDSS increase from T−1 to T0 (coeff. = 0.34, 95% CI = 0.22–0.45, p < 0.001) without a further change between T0 and T1 (p = 0.21). PMS patients with a time from conversion shorter than 2 years showed increased EDSS from T−1 to T0 (coeff. = 0.63, 95% CI = 0.18–1.08, p = 0.006) without a further change between T0 and T1 (p = 0.94), whereas PMS patients with a time from conversion longer than 2 years showed increased EDSS from T0 to T1 (coeff. = 0.30, 95% CI = 0.11–0.49, p = 0.002). Naïve patients showed an EDSS decrease between T0 and T1 (coeff. = −0.30, 95% CI = −0.50–−0.09, p = 0.004). In conclusion, our study highlighted that early ocrelizumab treatment is effective in modifying the disability accrual in MS patients.

Real-life evidence of treatment with alemtuzumab in patients diagnosed with relapsing-remitting multiple sclerosis in Colombia

Physical disability, cognitive impairment, depression, and fatigue are poorly understood in Latin American patients with multiple sclerosis following alemtuzumab infusion. To describe Sustained changes in physical disability in an average 22-month follow-up period after alemtuzumab infusion, and which demographical or clinical variables modulate change in EDSS, and adverse events, changes in cognition, fatigue, and depressive symptoms after an average 15-month follow-up period. Retrospective cohort observational study. Following the review of medical records, 23 patients with Relapsing Remitting Multiple Sclerosis treated with alemtuzumab were identified; of these, 17 had a baseline neuropsychological assessment and 12 had at least one follow-up neuropsychological assessment. Most of the patients presented a low level of physical disability, depression, fatigue, and cognitive impairment, which was more pronounced in the processing speed and visuospatial memory at baseline. Fifteen of 23 (65.2%) of patients showed disability improvement, 7 (30.1%) patients remained stable, and 1 (4.3%) patient worsened, and change was not influenced by age or baseline disability score. Twenty (87%) patients remained free of clinical relapses. Performance improved on the BVMT-R visual memory test, 9 (75%) remained stable or improved on the BICAMS, and 66.6% perceived decreased fatigue on the d-FIS. Adverse events occurred in 7 (30.1%) of patients, the most common were opportunistic infections in 2 (8.6%) patients, and one 29-year-old patient presented papillary thyroid carcinoma after infusion of the second course of alemtuzumab. Results suggest that treatment with alemtuzumab has a beneficial impact on disability, cognitive impairment, and perception of fatigue. The percentage and type of adverse events observed in the cohort are similar to those reported for other real-life studies.

Comparison of Mitoxantrone versus Cyclophosphamide Treatment in Patients with Secondary Progressive Multiple Sclerosis

Objective: Mitoxantrone (Mtx) and cyclophosphamide (Cyc) have successfully been used in highly aggressive multiple sclerosis (MS) patients. This study aims to compare the efficacy of these drugs in patients with secondary progressive MS (pwSPMS).&#x0D; Method: Clinical data of pwSPMS treated with either Mtx or Cyc were collected retrospectively. The EDSS scores before, during, and after the drug was determined. The efficacy of the drug was evaluated according to the EDSS change after the completion of therapy. The variations in clinical benefit between the two groups were investigated, as well as the factors that influenced them.&#x0D; Results: Fifty-nine SPMS patients (29 Mtx, 30 Cyc) were included in our study. Mean treatment periods were 19.5±9.9 months for Mtx and 9.1±4.1 months for the Cyc group. Mean EDSS in Mtx and Cyc groups at the first dose were 6.2±0.7 and 6.3±0.8, respectively (p=0.42). The percentage of patients who benefited from treatment was 41.6% in the Mtx group and 43.0% in the Cyc group (p=0.54). However, Mtx was more effective in patients with younger age of disease onset (p=0.01).&#x0D; Conclusion: Immunosuppression with intravenous Mtx and Cyc may equally prevent progression in patients with SPMS. Additionally, Mtx may be more beneficial in MS patients with earlier disease onset.

Evaluation of ocrelizumab in older progressive multiple sclerosis patients

BackgroundSeminal trials evaluating anti-CD20 therapy in progressive MS primarily found benefit in younger, less-disabled patients with more inflammatory disease activity. The risks and benefits of ocrelizumab use in older patients with progressive froms of MS are not known. MethodsRetrospective chart review was performed for patients older than 55 with primary or secondary progressive MS at the time of ocrelizumab initiation. Clinical endpoints from 2 years prior to anti-CD20 therapy served as a within-subject control. ResultsData was reviewed for 56 patients older than the age of 55 at the time of ocrelizumab initiation. Of 37 patients with 2-years of follow up on ocrelizumab, 40%(n=15) experienced confirmed disability progression (CDP) while 60% (n=22) remained stable or improved. 24 patients had data available for the within-subject control; for these patients, median age was 67, baseline EDSS 6.3, and disease duration 20.5 years. Prior to anti-CD20 therapy, 58% (n=14) of patients remained stable and 42% (n=10) experienced CDP. After ocrelizumab initiation, 71% (n=17) remained stable and 29% (n=7) experienced CDP. There was no difference between CDP (p=0.54) or change in EDSS (p=0.09) between time periods. Ocrelizumab was well tolerated and no difference in infection rate was seen using the within-subject control. ConclusionsWe found no difference in clinical endpoints for patients on ocrelizumab compared to prior to anti-CD20 therapy; however, we could not exclude a modest effect given our sample size. Larger trials are needed to evaluate ocrelizumab use in this understudied MS subpopulation.

Changes in Cerebrospinal Fluid Balance of TNF and TNF Receptors in Naïve Multiple Sclerosis Patients: Early Involvement in Compartmentalised Intrathecal Inflammation

An imbalance of TNF signalling in the inflammatory milieu generated by meningeal immune cell infiltrates in the subarachnoid space in multiple sclerosis (MS), and its animal model may lead to increased cortical pathology. In order to explore whether this feature may be present from the early stages of MS and may be associated with the clinical outcome, the protein levels of TNF, sTNF-R1 and sTNF-R2 were assayed in CSF collected from 122 treatment-naïve MS patients and 36 subjects with other neurological conditions at diagnosis. Potential correlations with other CSF cytokines/chemokines and with clinical and imaging parameters at diagnosis (T0) and after 2 years of follow-up (T24) were evaluated. Significantly increased levels of TNF (fold change: 7.739; p < 0.001), sTNF-R1 (fold change: 1.693; p < 0.001) and sTNF-R2 (fold change: 2.189; p < 0.001) were detected in CSF of MS patients compared to the control group at T0. Increased TNF levels in CSF were significantly (p < 0.01) associated with increased EDSS change (r = 0.43), relapses (r = 0.48) and the appearance of white matter lesions (r = 0.49). CSF levels of TNFR1 were associated with cortical lesion volume (r = 0.41) at T0, as well as with new cortical lesions (r = 0.56), whilst no correlation could be found between TNFR2 levels in CSF and clinical or MRI features. Combined correlation and pathway analysis (ingenuity) of the CSF protein pattern associated with TNF expression (encompassing elevated levels of BAFF, IFN-γ, IL-1β, IL-10, IL-8, IL-16, CCL21, haptoglobin and fibrinogen) showed a particular relationship to the interaction between innate and adaptive immune response. The CSF sTNF-R1-associated pattern (encompassing high levels of CXCL13, TWEAK, LIGHT, IL-35, osteopontin, pentraxin-3, sCD163 and chitinase-3-L1) was mainly related to altered T cell and B cell signalling. Finally, the CSF TNFR2-associated pattern (encompassing high CSF levels of IFN-β, IFN-λ2, sIL-6Rα) was linked to Th cell differentiation and regulatory cytokine signalling. In conclusion, dysregulation of TNF and TNF-R1/2 pathways associates with specific clinical/MRI profiles and can be identified at a very early stage in MS patients, at the time of diagnosis, contributing to the prediction of the disease outcome.

Long-term Clinical Outcomes of Hematopoietic Stem Cell Transplantation in Multiple Sclerosis.

To determine whether autologous hematopoietic stem cell transplantation (aHSCT) is able to induce durable disease remission in people with multiple sclerosis (MS), we analyzed the long-term outcomes after transplantation in a large cohort of patients with MS. To be included, a minimum dataset (consisting of age, MS phenotype, Expanded Disability Status Scale [EDSS] score at baseline, information on transplantation technology, and at least 1 follow-up visit after transplantation) was required. Two hundred ten patients were included (relapsing-remitting [RR] MS 122 [58%]). Median baseline EDSS score was 6 (1-9); mean follow-up was 6.2 (±5.0) years. Among patients with RRMS, disability worsening-free survival (95% confidence interval [CI]) was 85.5% (76.9%-94.1%) at 5 years and 71.3% (57.8%-84.8%) at 10 years. In patients with progressive MS, disability worsening-free survival was 71.0% (59.4%-82.6%) and 57.2% (41.8%-72.7%) at 5 and 10 years, respectively. In patients with RRMS, EDSS significantly reduced after aHSCT (p = 0.001; mean EDSS change per year -0.09 [95% CI -0.15% to -0.04%]). In patients with RRMS, the use of the BCNU+Etoposide+Ara-C+Melphalan (BEAM) + anti-thymocyte globulin (ATG) conditioning protocol was independently associated with a reduced risk of no evidence of disease activity 3 failure (hazard ratio 0.27 [95% CI 0.14-0.50], p < 0.001). Three patients died within 100 days from aHSCT (1.4%); no deaths occurred in patients transplanted after 2007. aHSCT prevents disability worsening in the majority of patients and induces durable improvement in disability in patients with RRMS. The BEAM + ATG conditioning protocol is associated with a more pronounced suppression of clinical relapses and MRI inflammatory activity. This study provides Class IV evidence that for people with MS, aHSCT induces durable disease remission in most patients.

PND51 Cladribine Tablets (CT) Versus Other Disease-Modifying Therapies in the Treatment of Relapsing-Remitting Multiple Sclerosis (RRMS) - Cost-Effectiveness Analysis.

To assess the cost-effectiveness of CT (Mavenclad®) as a treatment of high disease activity (HDA) RRMS, compared with alternative 1st line therapies in Poland: interferon beta-1a (IFN-b1a), interferon beta-1b (IFN-b1b), peginterferon beta-1a (pegIFN), dimethyl fumarate (DMF), glatiramer acetate (GA) and teriflunomide (TER). CT is a distinctive therapy in RRMS, mainly due to its unique dosage scheme. It is administered in 2 courses – 5-day cycles in 2 consecutive months at the beginning of each of 2 years of therapy. Patients have a good chance to be relieved from any regular MS treatment even over 4 years since the start of CT therapy. A global Markov model was adapted to reflect healthcare system in Poland. During lifetime horizon, in each subsequent 12-month cycle the cohort was at risk of experiencing disability progression, remission, no EDSS change, one or more relapses, or death. Clinical data was based on CLARITY and respective trials for comparators. Utilities were derived from literature. Direct medical costs from the public payer’s perspective were calculated. Assuming the CE threshold of 147,024 PLN/QALY, CT in the HDA RRMS population was the cost-effective strategy compared to most alternatives (ICUR values in relation to the threshold ranging from -14,6% to +0,9%). Only when CT vs GA or vs pegIFN were considered, the ICUR value slightly exceeded the threshold, but of less than 1%. Uncertainty was explored via deterministic and probabilistic sensitivity analyses, which confirmed robustness of the primary results. CT appears as cost-effective MS therapy in Poland, offering good value for money in the Polish healthcare system. Therefore the recent positive reimbursement decision for Mavenclad® issued for restricted population should be reconsidered in the future, so that more patients with HDA RRMS could benefit from CT use, that is firmly grounded in clinical evidence and supported by the financial estimates.

Serum neurofilament-light concentration and real-world outcome in MS

BackgroundPrognostication in multiple sclerosis (MS) remains challenging. Biomarkers capable of providing this information at diagnosis would be valuable in shaping therapeutic decisions. Measurement of neurofilament light (NfL) has shown promise in predicting clinical outcomes in established MS, but its ability to predict outcomes in real-world cohorts at diagnosis requires further validation. MethodsWe used linear regression to evaluate the relationship between serum NfL (sNfL), measured at the time of diagnosis with short-term (1-year) and medium-term (5-year) clinical outcomes in 164 people with MS from a real-world, population-based cohort. Cox proportional hazards regression was used to analyse the association between sNfL and subsequent hazard of relapse or sustained accumulation of disability (SAD). Analyses were adjusted for age and disease-modifying treatment (DMT). ResultssNfL concentration at diagnosis was modestly associated with baseline EDSS score (β = 0.272, 95% CI 0.051 to 0.494, p = 0.016). However, no significant associations were found between baseline sNfL and odds of relapse at 12-months, 5-year EDSS change, or the hazard of relapse or SAD over 5 years follow-up. Dichotomising baseline sNfL according to the median sNfL did not change these findings. ConclusionssNfL appears to be of limited clinical utility in predicting future irreversible neurological disability in a largely untreated real-world population, and remains insufficiently validated to shape treatment decisions at the time of diagnosis. Further studies may be needed for sNfL to be considered as a prognostic marker in the MS clinic. However the masking effect of DMTs on the natural disease trajectory will continue to pose challenges.

Efficacy of andrographolide in not active progressive multiple sclerosis: a prospective exploratory double-blind, parallel-group, randomized, placebo-controlled trial

BackgroundMultiple sclerosis (MS) is a chronic immune mediated disease and the progressive phase appears to have significant neurodegenerative mechanisms. The classification of the course of progressive MS (PMS) has been re-organized into categories of active vs. not active inflammatory disease and the presence vs. absence of gradual disease progression. Clinical trial experience to date in PMS with anti-inflammatory medications has shown limited effect. Andrographolide is a new class of anti-inflammatory agent, that has been proposed as a potential drug for autoimmune disorders, including MS.In the present trial, we perform an exploratory pilot study on the efficacy and safety of andrographolide (AP) compared to placebo in not active PMS.MethodsA pilot clinical trial using 140 mg oral AP or placebo twice daily for 24 months in patients with not active primary or secondary progressive MS was conducted. The primary efficacy endpoint was the mean percentage brain volume change (mPBVC). Secondary efficacy endpoints included 3-month confirmed disability progression (3-CDP) and mean EDSS change.ResultsForty-four patients were randomized: 23 were assigned to the AP group, and 21 were assigned to the placebo group. The median baseline EDSS of both groups was 6.0. Annualized mPBVC was − 0.679% for the AP group and − 1.069% for the placebo group (mean difference: -0.39; 95% CI [− 0.836–0.055], p = 0.08, relative reduction: 36.5%). In the AP group, 30% had 3-CDP compared to 41% in the placebo group (HR: 0.596; 95% CI [0.200–1.777], p = 0.06). The mean EDSS change was − 0.025 in the AP group and + 0.352 in the placebo group (mean difference: 0.63, p = 0.042). Adverse events related to AP were mild rash and dysgeusia.ConclusionsAP was well tolerated and showed a potential effect in reducing brain atrophy and disability progression, that need to be further evaluated in a larger clinical trial.Trial registrationClinicalTrials.gov NCT02273635 retrospectively registered on October 24th, 2014.

Volume loss in the deep gray matter and thalamic subnuclei: a longitudinal study on disability progression in multiple sclerosis.

Volume loss in the deep gray matter (DGM) has been reported in patients with multiple sclerosis (MS) already at early stages of the disease and is thought to progress throughout the disease course. To investigate the impact and predictive value of volume loss in DGM and thalamic subnuclei on disability worsening in patients MS over a 6-year follow-up period. Hundred and seventy-nine patients with RRMS (132 women; median Expanded Disability Status Scale, EDSS: 2.5) and 50 with SPMS (27 women; median EDSS: 4.5) were included in the study. Patients underwent annual EDSS assessments and annual MRI at 1.5T. DGM/thalamic subnuclei volumes were identified on high-resolution T1-weighted. A hierarchical linear mixed model for each anatomical DGM area and each thalamic subnucleus was performed to investigate the associations with disability scores. Cox regression was used to estimate the predictive properties of volume loss in DGM and thalamic subnuclei on disease worsening. In the whole sample and in RRMS, volumes of the thalamus and the striatum were associated with the EDSS; however, only thalamic volume loss was associated with EDSS change at follow-up. Regarding thalamic subnuclei, volume loss in the anterior nucleus, the pulvinar and the ventral anterior nucleus was associated with EDSS change in the whole cohort. A trend was observed for the ventral lateral nucleus. Volume loss in the anterior and ventral anterior nuclei was associated with EDSS change over time in patients with RRMS. Moreover, MS phenotype and annual rates of volume loss in the thalamus and ventral lateral nucleus were predictive of disability worsening. These results highlight the relevance of volume loss in the thalamus as a key metric for predicting disability worsening as assessed by EDSS (in RRMS). Moreover, the volume loss in specific nuclei such as the ventral lateral nucleus seems to play a role in disability worsening.

Switching from natalizumab to fingolimod treatment in multiple sclerosis: real life data from the Austrian MS Treatment Registry

To compare the efficacy of natalizumab (NTZ) and fingolimod (FTY) in the treatment of relapsing-remitting multiple sclerosis (MS) in sequential use in common and as a function of transition periods in a nationwide observational cohort using prospectively collected data from a real-life setting. We included 195 patients from the Austrian MS Treatment Registry, who had started treatment with NTZ at any time since 2006 and stayed on NTZ for at least 24months, switched afterwards within 1 year to FTY and stayed on FTY for at least another 12months. Transition periods between NTZ and FTY were grouped into three different intervals: < 3months (135 patients), 3-6months (44 patients), and 6-12months (16 patients). Estimated mean annualized relapse rates (ARR) over a mean treatment period of 44months were 0.26 for NTZ and 0.32 for FTY (p = 0.381) over 46months. In the treatment gap, differences were found concerning the relapse probability, seven (5.2%) patients in the < 3months group, six (13.6%) in thef 3-6months group, and seven (43.8%) in the 6-12months group (p < 0.001). After this treatment gap, no significant differences concerning ARR, EDSS change, EDSS progression, and regression were observed regardless the proceeding transition periods. Significantly higher efficacy of NTZ compared to FTY in sequential use was found regarding EDSS change, EDSS progression, and EDSS regression sustained for 12 and 24weeks. First, we here show an increased short-time risk for relapses during the treatment gap between NTZ and FTY therapy, dependent on the length of transition time. Second, the disease course after switching to FTY remained stable in the long-term evaluation. Therefore, switching from NTZ to FTY in a real-world setting appears efficacious and safe, but this data advocate for a short switching gap of 3months or less.

Use of glatiramer acetate between 2010\u20132015: effectiveness, safety and reasons to start GA as first or second line treatment in Swiss multiple sclerosis patients

BackgroundGlatiramer acetate (GA) is one of the first therapies approved for multiple sclerosis (MS). We prospectively included and monitored drug-naïve and pre-treated MS patients who had been prescribed GA for 1 year, to investigate reasons for GA prescription, its effectiveness and safety in real life clinical practice.MethodsOne year, prospective, multicentre, observational study performed between 2010 and 2015 in consecutive MS and clinically isolated syndrome patients starting GA as a first (“naïve”) or second (“switcher”) line therapy. Primary endpoint was the annualized relapse rate (ARR) over 1 year of GA treatment (from baseline, V1, to 12 months, V2) in naïve and switchers compared to previous 24 months. Secondary endpoints were: EDSS changes between V1 and V2, frequency of adverse events, and reasons for prescribing and discontinuing GA. Baseline demographics and clinical characteristics were retrieved from medical records, and outcome measures were documented at V1 and V2, and in case of clinical worsening.ResultsOne hundred ninety-four consecutive patients were monitored over 12 months (N = 64 naïve, N = 130 switchers). Side effect profile (naïve = 36%, switchers = 28%) and comorbidities (naïve = 31%, switchers = 15%) were the most frequent reasons to start GA. The ARR was reduced in both naïve and switchers during V1–2 as compared to the 24 months preceding V1 [naïve: 0.0 (0.0–0.0) vs 0.5 (0.5–1.0, p = 2.9e-10); switchers: 0.0 (0.0–0.0) vs 0.5 (0.0–0.5, p = 0.022)]. EDSS at V2 was significantly reduced only in naïve [(1.5 (1.0–2.5) vs 2.0 (1.5–2.5), p = 0.003)]. Naïve status and EDSS at V1 were negatively associated with EDSS change between V1-V2 in multivariable analysis (regression coefficient = − 0.436, p = 0.008, and regression coefficient = − 0.263, p = 6.18e-05, respectively). No new unexpected AE was reported.ConclusionIn our Swiss cohort, GA was prescribed mainly to naïve or switcher MS patients fearing interferon related side effects, with various comorbidities or considering pregnancy, and showed effectiveness and safety comparable with data of previous GA studies.