Secondary Progressive Multiple Sclerosis Research Articles

BAFF and APRIL signaling through B cell maturation antigen affects regulatory transitional B cells in multiple sclerosis.

Abstract Multiple sclerosis (MS) is a debilitating neuro-autoimmune disease that can be stratified into relapsing remitting (RR) MS, secondary progressive (SP) MS, and primary progressive (PP) MS. B cells can have both inflammatory and regulatory functions in MS. Transitional B cells are considered to have regulatory functions in MS. BAFF and APRIL, two cytokines, signals through the receptors BAFFR, TACI and BCMA and are thought to drive the regulatory function of transitional B cells. Here, we assessed the frequencies and expression of BAFFR, TACI and BCMA on the surface of regulatory transitional B cells in the blood of RRMS, PPMS and healthy individuals along with soluble versions of these receptors in the plasma. We found that transitional B cells were decreased in both RRMS and PPMS patients. The surface expression of BCMA was significantly lower on transitional B cells from RRMS patients but not PPMS patients compared to healthy individuals with no change in the expression of TACI and BAFFR. In addition, we found elevated levels of soluble BCMA in blood of PPMS patients but not RRMS patients compared to healthy and no difference in soluble BAFFR and TACI. Our data suggests that reduced BCMA signaling is associated with reduced numbers of transitional B cells in RRMS and PPMS. In RRMS, expression of BCMA is reduced on regulatory transitional B cells. In PPMS patients, there are higher levels of soluble BCMA which could act as a blocker of APRIL signaling through BCMA on the surface of transitional B cells. Altogether, our data suggests that reduced BCMA signaling in transitional B cells is contributing to the MS disease and the dysregulation of the BCMA signaling in RRMS and PPMS may be through a different mechanism. This study was supported by grants from the NMSS (RG-1602-07722), the NIH (R01AI137047 and R01EY027346) awarded to R.C. Axtell.

Therapeutic Strategies and Disease-Modifying Therapies for Multiple Sclerosis

Multiple sclerosis is an inflammatory demyelinating disease of unknown cause that affects the central nervous system. Although it was once deemed "incurable," many disease-modifying therapies have been introduced since the beginning of the 20th century; eight of these are now available in Japan. Treatment for multiple sclerosis is undergoing a significant shift from the safety-oriented "escalation strategy," in which the patient is initially administered medications with low risks of side effects but moderate efficacy, to a "personalized approach" based on individual prognostic factors followed by an "early top-down strategy" in which higher efficacy treatments are initiated first. Disease-modifying drugs for multiple sclerosis can be high- (fingolimod, ofatumumab, natalizumab) or moderate-efficacy (interferon beta, glatiramer acetate, dimethyl fumarate), and there are also disease-modifying therapies for secondary progressive multiple sclerosis (siponimod and ofatumumab). Approximately 20,000 Japanese patients have multiple sclerosis, and this number continues to increase. Many neurologists are expected to prescribe high-efficacy drugs in the future. The risk management of adverse events, particularly progressive multifocal leukoencephalopathy, is required to ensure that the importance of safety never be underestimated, even though treatment efficacy is the main focus.

The prevalence and incidence of multiple sclerosis over the past 20 years in northern Japan

The prevalence of multiple sclerosis (MS) in East Asia is thought to be lower than in Western countries. Globally, there is a trend of increasing MS prevalence. We investigated the changes in the prevalence and clinical phenotype of MS in the Tokachi province of Hokkaido in northern Japan, from 2001 to 2021. Data processing sheets were sent to all related institutions inside and outside the Tokachi area of Hokkaido island in Japan and were collected from April to May 2021. The prevalence according to the Poser's diagnostic criteria for MS was determined on March 31, 2021. In 2021, the crude MS prevalence in northern Japan was 22.4/100,000 (95% confidence interval, 17.6-28.0). The prevalences of MS standardized by the Japanese national population in 2001, 2006, 2011, 2016, and 2021 were 6.9, 11.5, 15.3, 18.5, and 23.3, respectively. The female/male ratio was 4.0 in 2021, increased from 2.6 in 2001. We checked the prevalence using the 2017 revised McDonald criteria, and found only additional male patient who had not fulfilled Poser's criteria. The age- and sex-adjusted incidence of MS per 100,000 individuals increased from 0.09 in 1980-1984 to 0.99 in 2005-2009; since then, it has remained stable. The proportions of primary-progressive, relapsing-remitting, and secondary-progressive MS types in 2021 were 3%, 82%, and 15%, respectively. Our results demonstrated a consistent increase in the prevalence of MS among the northern Japanese over 20 years, particularly in females, and consistently lower rates of progressive MS in northern Japan than elsewhere in the world.

A comprehensive review on multiple sclerosis: It’s etiology, symptoms, epidemiology and current therapeutic approaches

Multiple sclerosis is a chronic autoimmune, inflammatory neurological disease affecting the nervous system. It targets the myelin sheath of the axons and inflicts axonal degeneration. High susceptibility is seen in people of age group 20-40 years. The incidence rate is three times more in females compared to males. There are 4 types of multiple sclerosis, namely relapsing/remitting multiple sclerosis, secondary progressive multiple sclerosis, primary progressive multiple sclerosis, progressive relapsing multiple sclerosis with relapsing-remitting being the predominant type and makes up 85% of the cases. The pathogenesis of multiple sclerosis includes destruction of myelin sheath followed by formation of lesions and inflammation. Environmental factors and genetic variables play major role in development of the disease. Exposure to viral and bacterial agents can also lead to multiple sclerosis. Disease-modifying therapies (DMTs) are the most commonly employed management strategies for treating patients with multiple sclerosis. Conventional drugs like IFN-β-1a and glatiramer acetate are now being replaced by highly effective DMTs and autologous hematopoietic stem cell transplantation. Recently, there has been drastic developments in the management of multiple sclerosis, owing to the discovery of more tailored and individualized treatment protocols catering specifically to patient needs.

The therapeutic value of treatment for multiple sclerosis: analysis of health technology assessments of three European countries.

In accordance with European regulation, medicines containing a new active substance to treat neurodegenerative diseases as well as autoimmune and other immune dysfunctions must be approved by the European Medicines Agency (EMA) through the centralized procedure before they can be marketed. However, after EMA approval, each country is responsible for national market access, following the assessment performed by health technology assessment (HTA) bodies with regard to the therapeutic value. This study aims to provide a comparative analysis of HTA recommendations issued by three EU countries (France, Germany, and Italy) for new drugs for multiple sclerosis (MS) following EMA approval. In the reference period, we identified 11 medicines authorized in Europe for MS, including relapsing forms of MS (RMS; n = 4), relapsing-remitting MS (RRMS; n = 6), secondary progressive MS (SPMS; n = 1), and the primary progressive form (PPMS; n = 1). We found no agreement on the therapeutic value (in particular, the "added value" compared to the standard of care) of the selected drugs. Most evaluations resulted in the lowest score ("additional benefit not proven/no clinical improvement"), underlining the need for new molecules with better efficacy and safety profiles for MS, especially for some forms and clinical settings.

Cognitive and MRI Profiles in Primary and Secondary Progressive Multiple Sclerosis (P13-3.002)

<h3>Objective:</h3> We examined the neuropsychological profile of primary progressive (PP) and secondary progressive (SP) multiple sclerosis (MS) patients and investigated the relationship between cognitive functioning with structural and functional MRI abnormalities. <h3>Background:</h3> Studies comparing frequency and patterns of cognitive dysfunction between PPMS and SPMS have yielded conflicting results. <h3>Design/Methods:</h3> One-hundred eighty-three MS patients (60 PPMS and 123 SPMS) and 75 age- and sex-matched healthy controls underwent 3.0T MRI. MS patients were administered the Brief Repeatable Battery of Neuropsychological tests (BRB-N) and were classified as cognitively impaired if they scored below the 5^th percentile of the normative sample on at least two tests. Four cognitive domain z-scores were determined from normative data, and then averaged to obtain a measure of global cognition (z-BRB-N). Using hierarchical linear regression analysis, the contribution of lesion volumes, normalized brain volumes, white matter fractional anisotropy (FA) and mean diffusivity (MD) abnormalities, and resting state (RS) functional connectivity (FC) alterations to global cognition in PPMS and SPMS was investigated. <h3>Results:</h3> Patients with PPMS and SPMS had similar z-scores in all investigated cognitive domains. Compared to PPMS, SPMS showed decreased FA and increased MD in the fornix, and lower RS FC within the basal ganglia network. The frequency of cognitive impairment was 31.7% in PPMS and 41.3% in SPMS (p=0.19). In PPMS, poorer cognitive performance (e.g., lower z-BRB-N) was associated with decreased FA of the medial lemniscus (ΔR²=0.11; p=0.011) and lower normalized gray matter volume (ΔR²=0.29; p&lt;0.001). In SPMS, poorer cognitive performance was associated with decreased FA of the fornix (ΔR²=0.35; p&lt;0.001) and lower normalized white matter volume (ΔR²=0.05; p=0.034). <h3>Conclusions:</h3> PPMS and SPMS had similar neuropsychological profile. Cognitive dysfunction in PPMS and SPMS was related to distinct patterns of structural MRI abnormalities and involvement of different white matter tracts, while RS FC alterations did not contribute to explain their global cognitive functioning. <b>Disclosure:</b> Damiano Mistri has nothing to disclose. Ms. Cacciaguerra has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Ms. Cacciaguerra has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for BMS Celgene. Ms. Cacciaguerra has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi. Ms. Cacciaguerra has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for BIOMEDIA. Paola Valsasina has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for ACCMED. Elisabetta Pagani has nothing to disclose. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bristol Myers Squibb . Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi Genzyme. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Maria Assunta Rocca has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva. The institution of Maria Assunta Rocca has received research support from Italian Ministry of Health, MS Society of Canada and Fondazione Italiana Sclerosi Multipla. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA).

Gut microbiota composition in untreated people with relapsing-remitting and secondary-progressive Multiple Sclerosis (P2-3.008)

<h3>Objective:</h3> To investigate prospectively the qualitative&amp;quantitative differences in the faecal bacterial composition of untreated patients with RRMS and SPMS. <h3>Background:</h3> Alterations in gut microbiome composition are suggested to act as a driver in the transition of RRMS to secondary-progressive MS (SPMS). <h3>Design/Methods:</h3> We present prospective 16S rRNA gene high-throughput sequencing data from faecal samples of 33 patients with RRMS and 10 patients with SPMS. Differences between gut microbiota composition were validated prospectively at three time-points over 12-months. We used available microbial profiles of healthy controls and RRMS from a different population (Jangi-et-al.2016) for comparative analyses with our own data. We studied blood T regulatory cell (CD4+CD25highFoxp3+) associations with specific gut bacterial taxa. <h3>Results:</h3> While some gut microbiota composition traits were common to RRMS and SPMS patients, we identified a small number of distinctive bacteria associated with SPMS; of these, the genus Slackia. Slackia exigua is known to be part of gut dysbiosis associated with cancer progression. There were no significant correlations between Treg counts and abundance of selected bacterial taxa significantly associated with RRMS or SPMS. <h3>Conclusions:</h3> Subtle differences were observed between the gut bacterial composition of SPMS patients and that of RRMS. <b>Disclosure:</b> Dr. Tanasescu has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Johnson &amp; Johnson Romania. Dr. Tanasescu has received research support from UK MRC grant MR/T024402/1. The institution of Ms. Cortés Carbonell has received research support from Royal Society. David Pritchard has nothing to disclose. Prof. Cantacessi has nothing to disclose. Dr. Constantinescu has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. Dr. Constantinescu has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Dr. Constantinescu has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Novartis. The institution of Dr. Constantinescu has received research support from Nottingham University Hospital Charity.

AMA-VACC: Clinical trial assessing the immune response to SARS-CoV-2 mRNA vaccines and booster vaccination in siponimod treated patients with secondary progressive multiple sclerosis (P12-3.004)

<h3>Objective:</h3> We are aiming to understand the cellular and humoral immune responses to SARS-CoV-2 mRNA booster vaccinations in siponimod treated patients. <h3>Background:</h3> SARS-CoV-2 mRNA vaccines are a key factor fighting the COVID-19 pandemic across the globe. However, data are lacking on the efficacy of vaccination in patients with secondary progressive multiple sclerosis (SPMS) on disease-modifying therapies (DMTs) both over time and after a booster vaccination. <h3>Design/Methods:</h3> AMA-VACC is an open-label, three-cohort, prospective study in Germany with 41 multiple sclerosis patients currently treated with siponimod, any first-line DMT or without treatment at all in clinical routine. Cohort 1 receives SARS-CoV-2 mRNA vaccination while continuing their current siponimod treatment, cohort 2 interrupts siponimod treatment for the purpose of a full vaccination cycle and cohort 3 receives vaccination during continuous treatment with first-line DMTs (glatirameracetate, interferons, teriflunomide) or no current treatment in clinical routine. Primary endpoint is the rate of patients achieving seroconversion assessed by detection of serum neutralizing antibodies one week after SARS-CoV-2 mRNA vaccination. Furthermore, development and maintenance of SARS-CoV-2 specific T-cells is evaluated in all patients. Both parameters are analyzed in week one, month one and six month after initial vaccination cycle and one month after a booster vaccination. <h3>Results:</h3> After a positive first interim analysis showing both SARS-CoV-2 neutralizing antibodies and T-cell responses one week after complete vaccination in siponimod patients, final data of the study will be available in early 2023 including the effect of booster vaccination, which was received by 38 of 41 patients during study. <h3>Conclusions:</h3> This final analysis of the AMA-VACC trial will provide first longitudinal data on the immune response after SARS-CoV-2 mRNA vaccination and booster vaccination in siponimod treated SPMS patients and support physicians and patients to make an informed decision on the coordination of SARS-CoV-2 mRNA vaccination and SPMS treatment. <b>Disclosure:</b> Dr. Ziemssen has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Dr. Ziemssen has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Roche. Dr. Ziemssen has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. Dr. Ziemssen has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for BMS Celgene. Dr. Ziemssen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck. Dr. Ziemssen has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Roche. Dr. Ziemssen has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Novartis. Dr. Ziemssen has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Dr. Ziemssen has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Sanofi. Dr. Ziemssen has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for BMS Celgene. Dr. Ziemssen has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Biogen. Dr. Ziemssen has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for TEVA. The institution of Dr. Ziemssen has received research support from Biogen. The institution of Dr. Ziemssen has received research support from Novartis. The institution of Dr. Ziemssen has received research support from Merck. The institution of Dr. Ziemssen has received research support from Sanofi. The institution of Dr. Ziemssen has received research support from Celgene. Dr. Groth has received personal compensation for serving as an employee of Novartis Pharma GmbH. Dr. Winkelmann has received personal compensation for serving as an employee of Novartis Pharma GmbH. Prof. Bopp has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. Prof. Bopp has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Prof. Bopp has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Teva. Prof. Bopp has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Merck. Prof. Bopp has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pathios Therapeutics. The institution of Prof. Bopp has received research support from DFG (German Research Foundation). The institution of Prof. Bopp has received research support from BMBF. Prof. Bopp has received intellectual property interests from a discovery or technology relating to health care.

Siponimod Stabilizes Physical Disability Scores in People Living With Secondary Progressive Multiple Sclerosis After 2 Years of Treatment: Analysis From the Novartis Global Managed Access Program (P8-3.010)

<h3>Objective:</h3> To describe demographic and clinical characteristics and characterize change in Expanded Disability Status Scale (EDSS) score in people living with secondary progressive multiple sclerosis (plwSPMS) receiving siponimod under the managed access program (MAP; Global Siponimod MAP cohort [BAF2001M cohort]). <h3>Background:</h3> Siponimod significantly reduced the risk of confirmed disability progression and worsening of cognitive processing speed vs placebo in the phase 3 EXPAND trial (NCT01665144). However, real-world effectiveness data for siponimod remain scarce. <h3>Design/Methods:</h3> The BAF2001M cohort is an umbrella program to facilitate access to siponimod when marketing authorization is pending (under physician request) in the absence of acceptable alternative treatments. The program started in March 2019 and is ongoing. The target population included adult patients with SPMS and an EDSS score &lt;7 from March 2019 to January 2021. After January 2021, access to the MAP required SPMS with active disease. Treatment selection and patient monitoring were based on physician assessment. Baseline characteristics included country, age, sex, relapse, MRI activity in the last 2 years, EDSS, and cognition evaluation. <h3>Results:</h3> A total of 632 cases were analyzed (153 excluded from analysis due to local country restrictions). Mean (SD) age was 52.3 (8.7) years, 60% of patients were female, and median (IQR) EDSS was 5.5 (4.5–6.5). Prior to siponimod start, ~51% experienced a relapse in the last 2 years, 54% had previous cognitive evaluation, and 52% had an MRI scan in the last 2 years (48% showed activity). Mean change in EDSS from baseline was approximately −0.02/−0.03 at Months 6, 12, 18, and 24 (not significantly different vs baseline). Approximately 94% (140/149) of patients improved or were stable at Month 24. <h3>Conclusions:</h3> Most plwSPMS demonstrated improved or stabilized EDSS scores over 2 years. This population was older than the EXPAND study population and around half demonstrated relapse/MRI activity. Results support the effectiveness of siponimod in SPMS. <b>Disclosure:</b> Dr. Mavrikis Cox has received personal compensation for serving as an employee of Novartis Pharmaceuticals. Dr. Mavrikis Cox has stock in Novartis Pharmaceuticals. Virginia DeLasHeras has nothing to disclose. Dr. Ryan has received personal compensation for serving as an employee of Novartis. Mrs. Istrate has nothing to disclose. Soudeh Ansari has received personal compensation for serving as an employee of Novartis. Sophie Arnould has nothing to disclose. Dr. Piani Meier has received personal compensation for serving as an employee of Novartis. Dr. Piani Meier has received personal compensation for serving as an employee of Merck Group.

Myelin Density in Normal-Appearing White Matter in Measurements by q-Space Diffusional MRI Correlates with Clinical Disability in Multiple Sclerosis (P10-3.005)

Myelin Density in Normal-Appearing White Matter in Measurements by q-Space Diffusional MRI Correlates with Clinical Disability in Multiple Sclerosis (P10-3.005)

Effect of RIPK1 Inhibitor, SAR443820, on Serum Neurofilament Light Levels in Patients with Multiple Sclerosis: A Phase 2 Trial Design (P6-3.011)

Effect of RIPK1 Inhibitor, SAR443820, on Serum Neurofilament Light Levels in Patients with Multiple Sclerosis: A Phase 2 Trial Design (P6-3.011)

Cognitive Processing Speed Predicts Disability Milestones in Multiple Sclerosis (P5-3.014)

Cognitive Processing Speed Predicts Disability Milestones in Multiple Sclerosis (P5-3.014)

Changing Treatment Trends for MS Patients Recently Initiated on Their First DMT (P12-3.012)

<h3>Objective:</h3> To evaluate if disease-modify therapy (DMT) choice has changed for treatment-naïve multiple sclerosis (MS) patients from 2020–2022. <h3>Background:</h3> Cross-sectional audit of MS patients was conducted annually. Data were reviewed by an independent market intelligence agency which specializes in tracking the neurology market. <h3>Design/Methods:</h3> US neurologists (2020: N=199; 2021: N=205; 2022: N=208) completed a survey and contributed chart reviews for a retrospective, cross-sectional audit on MS patients who started their first DMT within the prior 3 months (2020: N=1,006; 2021: N=1,018; 2022: N=1,095). MS patients were analysed as a whole, as well as by physician-reported MS subtypes for relapsing-remitting MS (RRMS; N=722, N=768, N=827), active secondary progressive MS (aSPMS; N=74, N=50, N=59), and primary progressive MS (PPMS; N=92, N=69, N=72). <h3>Results:</h3> Overall use of glatiramer acetate (GA) (32% in 2020, 16% in 2022) has declined; use of fumarate agents (13%, 21%) and anti-CD20 monoclonal antibody (mAb) DMTs (13%, 21%) expanded. Interferon (13% in 2020 and 2022) and S1P receptor modulator class (12%, 14%) use has remained stable. Use of both brand (18%, 11%) and generics (14%, 6%) of GA declined. For fumarates, use has shifted from branded dimethyl fumarate (DMF; 13%, 8%) to generic DMF (0%, 6%) and diroximel fumarate (0%, 6%). For S1Ps, use has shifted from fingolimod (10%, 6%) to ozanimod (0%, 4%) and ponesimod (0%, 1%). Changes in DMT use are similar for RRMS: GA use declined (31%, 16%); fumarates (17%, 23%) and anti-CD20 mAb DMT (9%, 19%) use expanded. GA use also declined for aSPMS (30%, 7%) and PPMS (30%, 8%); anti-CD20 mAb DMT use grew for aSPMS (19%, 41%). <h3>Conclusions:</h3> DMT prescribing trends are evolving for MS patients recently initiated on their first DMT. Use of GA agents has fallen across MS subtypes, while use of the high-efficacy anti-CD20 mAb DMT class has expanded. <b>Disclosure:</b> Dr. McFadden has nothing to disclose.

Patterns and Predictors of Multiple Sclerosis Phenotype Transitions: A Longitudinal Analysis Using the CLIMB Study (P5-3.018)

Patterns and Predictors of Multiple Sclerosis Phenotype Transitions: A Longitudinal Analysis Using the CLIMB Study (P5-3.018)

Real-world use of natalizumab in Austria: data from the Austrian Multiple Sclerosis Treatment Registry (AMSTR)

IntroductionWith the approval of natalizumab in Europe in 2006, the Austrian Multiple Sclerosis Therapy Registry (AMSTR) was established. Here, we present data from this registry about effectiveness and safety of natalizumab in patients treated up to 14 years.Patients/methodsData retrieved from the AMSTR contained baseline characteristics and biannual documentation of annualised relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score as well as adverse events and reasons for discontinuation on follow-up visits.ResultsA total of 1596 natalizumab patients (71% women, n = 1133) were included in the analysis and the observed treatment duration ranged from 0 to 164 months (13.6 years). The mean ARR was 2.0 (SD = 1.13) at baseline, decreasing to 0.16 after 1 year and 0.01 after 10 years. A total of 325 patients (21.6%) converted to secondary progressive multiple sclerosis (SPMS) during the observational period. Of 1502 patients, 1297 (86.4%) reported no adverse events (AE) during follow-up visits. The most common reported AEs were infections and infusion-related reactions. John Cunningham virus (JCV) seropositivity was the most common specified reason for treatment discontinuation (53.7%, n = 607). There were five confirmed cases of Progressive Multifocal Leukoencephalopathy (PML) with 1 death.ConclusionThe effectiveness of natalizumab in patients with active relapsing–remitting multiple sclerosis (RRMS) could be confirmed in our real-world cohort even after follow-up of up to 14 years, though after year 10, there were less than 100 remaining patients. A low number of AE were reported in this nationwide registry study, establishing Natalizumab’s favourable safety profile during long-term use.

Influence of Residual Quadrupolar Interaction on Quantitative Sodium Brain Magnetic Resonance Imaging of Patients With Multiple Sclerosis.

The purpose of this work was to evaluate the influence of residual quadrupolar interaction on the determination of human brain apparent tissue sodium concentrations (aTSCs) using quantitative sodium magnetic resonance imaging ( 23 Na MRI) in healthy controls (HCs) and patients with multiple sclerosis (MS). Especially, it was investigated if the more detailed examination of residual quadrupolar interaction effects enables further analysis of the observed 23 Na MRI signal increase in MS patients. 23 Na MRI with a 7 T MR system was performed on 21 HC and 50 MS patients covering all MS subtypes (25 patients with relapsing-remitting MS, 14 patients with secondary progressive MS, and 11 patients with primary progressive MS) using 2 different 23 Na pulse sequences for quantification: a commonly used standard sequence (aTSC Std ) as well as a sequence with shorter excitation pulse length and lower flip angle for minimizing signal loss resulting from residual quadrupolar interactions (aTSC SP ). Apparent tissue sodium concentration was determined using the same postprocessing pipeline including correction of the receive profile of the radiofrequency coil, partial volume correction, and relaxation correction. Spin dynamic simulations of spin-3/2 nuclei were performed to aid in the understanding of the measurement results and to get deeper insight in the underlying mechanisms. In normal-appearing white matter (NAWM) of HC and all MS subtypes, the aTSC SP values were approximately 20% higher than the aTSC Std values ( P < 0.001). In addition, the ratio aTSC SP /aTSC Std was significantly higher in NAWM than in normal-appearing gray matter (NAGM) for all subject cohorts ( P < 0.002). In NAWM, aTSC Std values were significantly higher in primary progressive MS compared with HC ( P = 0.01) as well as relapsing-remitting MS ( P = 0.03). However, in contrast, no significant differences between the subject cohorts were found for aTSC SP . Spin simulations assuming the occurrence of residual quadrupolar interaction in NAWM were in good accordance with the measurement results, in particular, the ratio aTSC SP /aTSC Std in NAWM and NAGM. Our results showed that residual quadrupolar interactions in white matter regions of the human brain have an influence on aTSC quantification and therefore must be considered, especially in pathologies with expected microstructural changes such as loss of myelin in MS. Furthermore, the more detailed examination of residual quadrupolar interactions may lead to a better understanding of the pathologies themselves.

Disability accrual in primary and secondary progressive multiple sclerosis

BackgroundSome studies comparing primary and secondary progressive multiple sclerosis (PPMS, SPMS) report similar ages at onset of the progressive phase and similar rates of subsequent disability accrual. Others report later...

Autonomic response to walk tests is useful for assessing outcome measures in people with multiple sclerosis.

Objective: The aim of this study was to evaluate the association between changes in the autonomic control of cardiorespiratory system induced by walk tests and outcome measures in people with Multiple Sclerosis (pwMS). Methods: Electrocardiogram (ECG) recordings of 148 people with Relapsing-Remitting MS (RRMS) and 58 with Secondary Progressive MS (SPMS) were acquired using a wearable device before, during, and after walk test performance from a total of 386 periodical clinical visits. A subset of 90 participants repeated a walk test at home. Various MS-related symptoms, including fatigue, disability, and walking capacity were evaluated at each clinical visit, while heart rate variability (HRV) and ECG-derived respiration (EDR) were analyzed to assess autonomic nervous system (ANS) function. Statistical tests were conducted to assess differences in ANS control between pwMS grouped based on the phenotype or the severity of MS-related symptoms. Furthermore, correlation coefficients (r) were calculated to assess the association between the most significant ANS parameters and MS-outcome measures. Results: People with SPMS, compared to RRMS, reached higher mean heart rate (HRM) values during walk test, and larger sympathovagal balance after test performance. Furthermore, pwMS who were able to adjust their HRM and ventilatory values, such as respiratory rate and standard deviation of the ECG-derived respiration, were associated with better clinical outcomes. Correlation analyses showed weak associations between ANS parameters and clinical outcomes when the Multiple Sclerosis phenotype is not taken into account. Blunted autonomic response, in particular HRM reactivity, was related with worse walking capacity, yielding r = 0.36 r = 0.29 (RRMS) and r > 0.5 (SPMS). A positive strong correlation r > 0.7 r > 0.65 between cardiorespiratory parameters derived at hospital and at home was also found. Conclusion: Autonomic function, as measured by HRV, differs according to MS phenotype. Autonomic response to walk tests may be useful for assessing clinical outcomes, mainly in the progressive stage of MS. Participants with larger changes in HRM are able to walk longer distance, while reduced ventilatory function during and after walk test performance is associated with higher fatigue and disability severity scores. Monitoring of disorder severity could also be feasible using ECG-derived cardiac and respiratory parameters recorded with a wearable device at home.

The evaluation of small fibers in multiple sclerosis

Dysesthetic or ongoing extremity pain is a common symptom in all multiple sclerosis (MS) types. Although the pathology of the disease is the demyelination of central neurons, the patients may also complain of neuropathic pain in distal extremities that is generally related to A-delta and C fiber dysfunction. It is not known whether thinly myelinated and unmyelinated fibers are affected in MS patients. We aim to investigate the small fiber loss and its length dependency. We evaluated the skin biopsy taken from proximal and distal leg of MS patients with neuropathic pain. Six patients with primary progressive MS (PPMS), seven with relapsing-remitting MS (RRMS), seven with secondary progressive MS (SPMS) and as a control group ten age and sex-matched healthy controls were included. Neurological examination, electrophysiological evaluation and DN4 questionnaire were performed. Subsequently, skin punch biopsy from 10 cm above the lateral malleolus and proximal thigh were done. The biopsy samples were stained with PGP9.5 antibody and intraepidermal nerve fiber density (IENFD) was determined. The mean proximal IENFD was 8.58±3.58 fibers/mm among MS patients and 14.72±2.89 fiber/mm among healthy controls (p=0.001). However, the mean distal IENFD did not differ between MS patients and healthy controls (9.26±3.24 and 9.75±1.6 fiber/mm respectively. Although proximal and distal IENFD tends to be lower in MS patients with neuropathic pain, there was no statistically significant difference between MS patients with and without neuropathic pain CONCLUSION: Although MS is a demyelinating disease, unmyelinated fibers can also be affected. Our findings suggest non-length dependent small fiber neuropathy in MS patients.

Exploring physicians’ prescribing behavior in patients with multiple sclerosis in Saudi Arabia: a sequential explanatory mixed-methods

BackgroundMultiple sclerosis (MS) is the most common disabling neurological disease in young adults worldwide with majority of patients manifest symptoms between 20 and 40 years of age. The aims of this study are to explore physicians’ perspectives, views, and behaviors in diagnosing and treating patients with MS in Saudi Arabia and investigate the prescribing pattern of disease-modifying therapies (DMTs).MethodsA sequential explanatory mixed-method approach was used to achieve the study objectives. The quantitative arm of the study consisted of patient data extracted from the Saudi MS registry from 2015 to 2018. The qualitative study consisted of in-depth semi-structured interviews with physicians using a validated interview topic guide comprising 28 open-ended questions.ResultsWe extracted data of 2,507 patients from 20 different hospitals across Saudi Arabia. Patients’ mean age was 34 ± 10 years; two-thirds (n = 1,668) were female. 92% (n = 2,292) had relapsing-remitting multiple sclerosis, and 5% (n = 126) had secondary-progressive multiple sclerosis. In general, patients with MS received at least one drug as the DMT or DMTs and corticosteroids for those with relapse. Qualitatively, nine physicians agreed to participate in the interviews. Of them, five (55%) were male and four were female from different regions. Thematic analysis yielded three main themes: practice, views, and challenges.ConclusionsThe prevalence of MS in Saudi Arabia is raising but is still much lower than that reported in the Gulf region. A national MS guideline is needed to streamline diagnosis and treatment criteria, avoid any delay in treatment, and guide physicians who provide care for patients with MS.