Hospital Universitario Ramón y Cajal
Department of Neurology

Author Of 1 Presentation

Disease Modifying Therapies – Risk Management Oral Presentation

PS09.03 - Predictive biomarkers of the development of autoimmunity in patients treated with alemtuzumab

Speakers
Presentation Number
PS09.03
Presentation Topic
Disease Modifying Therapies – Risk Management
Lecture Time
09:45 - 09:57

Abstract

Background

Alemtuzumab has proven to be an effective treatment for patients with highly active multiple sclerosis (MS). However, its use has been limited by adverse events (AEs) as secondary autoimmunity, being the most frequent those involving the thyroid gland, observed in around 40% of patients.

Objectives

To explore whether patient blood lymphocyte profile before alemtuzumab treatment initiation can identify patients with an increased risk of developing later autoimmunity.

Methods

A multicentre prospective longitudinal study was performed, including fifty‐four Relapsing-Remitting MS (RRMS) patients diagnosed in five Spanish hospitals. Patient blood samples were collected before initiating treatment with alemtuzumab. Autoimmune AEs were defined as the development, at any point within 2 years of follow-up, of any autoimmune thyroid-associated event, immune thrombocytopenia and/or autoimmune nephropathy. Differences were assessed using Man-Whitney U tests. Cut-off values were established using ROC curves to predict autoimmune AEs. Odds ratios were calculated by Fisher tests.

Results

Fifty‐four RRMS patients, 36 (66.7%) women, with a median (range) age of 28 (13–67) years and median (range) follow-up of 6 (0-20) years. Fourteen patients (25.9%) experienced autoimmune AEs, and all of them were dysthyroidism. No immune thrombocytopenia or nephropathies were observed. No statistical differences were found in clinical and demographic characteristics between patients who developed autoimmune AEs and those who did not. Patients who experienced autoimmune AEs before treatment onset had a higher percentage of blood CD19+ B cells (p=0.001), with a higher relative percentage of naïve B cells and plasmablasts. When explored total cell numbers, only plasmablast levels remained significant (p=0.02). A lower risk of autoimmune AEs after alemtuzumab was observed among patients with less than 7.6% of blood CD19+ B cells [odds ratio (OR) 16, confidence interval (CI) 3.86–58.95, p<0.0001] or less than 0.13% of plasmablast cells [OR 9.33, CI 2.17–42.65, p=0.002].

Conclusions

A low percentages of blood CD19+ B cells or plasmablasts before Alemtuzumab treatment predicted a lower risk of autoimmune AEs.

Collapse

Author Of 10 Presentations

Epidemiology Poster Presentation

LB1166 - Risk and outcomes of COVID-19 in patients with multiple sclerosis in Madrid Spain  (ID 1480)

Abstract

Background

Infections are an important cause of hospitalization in patients with MS. Data on outcomes of COVID-19 in patients with MS are limited

Objectives

To quantify the risks of infection, hospitalization, admission to intensive care and death due to SARS-CoV-2 infection among patients with MS relative to the general population, and to identify factors associated with risk of hospitalization

Methods

A regional registry was created to collect data on incidence, hospitalization rates, intensive care unit (ICU) admission and death in patients with MS and COVID-19. National government outcomes and seroprevalence data were used for comparison.

Results

Two-hundred nineteen patients with MS were included in the registry, 51 of whom were hospitalized. The infection incidence rate (IR) was lower in patients with MS than the general population (adjusted IR ratio 0.78; 95% confidence interval: 0.70–0.80), but hospitalization rates were higher (adjusted relative risk 6.52 [6.13–7.04]). Disease severity was generally low, with only one ICU admission and five deaths. Males with MS had higher incidence rates and risk of hospitalization than females. No association was found between the use of any disease-modifying therapy (DMT) and hospitalization risk.

Conclusions

Patients with MS do not appear to have greater risks of SARS-CoV-2 infection or severe COVID-19 outcomes compared with the general population. The decision to start or continue DMT should be based on a careful risk-benefit assessment.

Collapse
Biomarkers and Bioinformatics Poster Presentation

P0066 - Dimethyl fumarate decreases serum neurofilament light chain in relapsing-remitting multiple sclerosis patients. (ID 924)

Presentation Number
P0066
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Serum neurofilament light chain (sNfL) levels are associated with disease activity and prognosis in relapsing-remitting multiple sclerosis (RRMS) patients. Treatment with second-line disease modifying therapies (DMTs) leads to a reduction of sNfL, but little is known regarding first-line DMTs as dimethyl fumarate (DMF).

Objectives

To explore changes of sNfL levels in RRMS patients during treatment with DMF. To evaluate the potential role of sNfL measurement to predict an optimal treatment response.

Methods

Blood samples from 64 consecutive RRMS patients initiating DMF at Hospital Universitario Ramón y Cajal were collected at baseline and at 3, 6 and 12 months thereafter. sNfL levels were measured using a sensitive Single Molecular Array (SIMOA) assay (Quanterix). Patients were classified into No Evidence of Disease Activity (NEDA) and Ongoing Disease Activity (ODA) according the presence/absence of relapses, EDSS progression and/or MRI activity during the first year.

Results

Age at treatment initiation was 40.6 [33.2-46.3] years (median [25-75%IQR]) and EDSS was 1.5 [1.5-2.5]. Forty eight (75%) patients received other previous DMTs, seven of them were second-line DMTs. 66% of patients had evidence of disease activity at DMF initiation. Baseline sNfL levels were higher in patients who had evidence of disease activity at that time compared with patients who had not (12.2 pg/ml Vs. 8.8 pg/ml, p=0.024). No differences were found in baseline sNfL levels between naïve and previously treated patients, or between patients treated with first and second line DMTs. After 12 months of DMF treatment, 44 (69%) patients were NEDA and 20 (31%) were ODA. Baseline sNfL levels were higher in ODA patients compared to NEDA patients (14.6 pg/ml Vs. 9.2 pg/ml, p=0.016). A cut-off value of 12 pg/ml was established to predict NEDA status (OR=4.7; 95%CI: 1.6–15.7; p=0.008). After one year of DMF, sNfL levels decreased by 34.4% (p<0.0001). Both NEDA and ODA patients experienced a progressive sNfL reduction during the first year of treatment. However, this reduction was observed earlier in NEDA patients (three months after DMF initiation) than in ODA patients (six months).

Conclusions

DMF induced a progressive decrease in sNfL concentration during the first year of treatment. This reduction was delayed in ODA patients. Patients with basal sNFL values ≤ 12 pg/ml showed increased probability to achieve NEDA status at 12 months.

Collapse
Biomarkers and Bioinformatics Poster Presentation

P0172 - The prognostic value of lipid-specific IgM oligoclonal bands versus IgM index in patients with a clinical isolated syndrome: a comparative study. (ID 1114)

Speakers
Presentation Number
P0172
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

The value of intrathecal IgM synthesis (ITMS) is increasingly recognized as a prognostic biomarker in patients with a clinically isolated syndrome (CIS). However, no comparative studies between different methods to assess ITMS have been described previously evaluating the prognosis of patients with CIS.

Objectives

To compare the predictive value of IgM Reibergram (IR) and the presence of lipid-specific IgM oligoclonal bands (LS-OCMB) in CSF to predict conversion to clinically defined multiple sclerosis (CDMS), and the onset of EDSS of 3, 6 and a secondary progressive MS (SPMS).

Methods

An observational single-center study with CIS patients with at least 2 years of follow-up attended at Hospital Universitario Ramón y Cajal was performed. Demographics, clinical, radiological and immunological variables were collected.

Results

196 patients were included, 131 (66.8%) women, with a median (range) age of 31 (12–63) years and mean (SD) follow-up of 13.2 (±7.0) years. Overall, positive LS-OCMB was observed in 52 (26.5%) patients and IR in 32/193 (16.6%), reaching a concordance of 59.4% between both. The risk of CDMS was significantly higher exclusively among LS-OCMB (adjusted HR 1.80 (95%CI 1.24-2.62), p=0.002), but not for IR. In addition, LS-OCMB predicted a higher risk of reaching an EDSS of 3 (OR 1.97, p=0.044), an EDSS of 6 (OR 3.82, p=0.001) and a SPMS (OR 2.67, p=0.013) among MS patients. No significant differences were observed with IR.

Conclusions

LS-OCMB are a more sensitive and reliable CSF biomarker to predict the natural history of CIS patients compare to semi-quantitative IR.

Collapse
Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0248 - Consensus guidelines for the timely detection and diagnosis of disease progression in multiple sclerosis patients (ID 1328)

Abstract

Background

Secondary Progressive Multiple Sclerosis (SPMS) is a clinical form of MS characterized by gradual accrual of disability independent of relapses over time. Limited information is available on decision-making in the management of MS. As a consequence, it is frequently diagnosed retrospectively, thus reducing treatment options.

Objectives

To establish consensus on patient monitoring and definition of relevant clinical variables that can support decision making in the early identification and management of disease progression.

Methods

A two-round RAND-UCLA method was used, involving a panel of 15 MS specialists in Spain. A questionnaire consisting of 72 open-ended questions from 3 dimensions (clinical, radiological and biomarkers) was circulated to the experts in Round I. Eleven additional items were included in Round II based on panel feedback in Round I. Items were rated on a 4-point Likert scale and consensus was defined as ≥66% agreement on an item. Final data are presented.

Results

Panellists agreed on the need of monitoring the patients remaining clinically and radiologically stable while on immunomodulators (93%) or immunosuppressors (73%) every 6 months, leaving the special situations to clinical judgement (80% and 93%, respectively). EDSS is the best variable to define progression (93%); six months is the minimum time to confirm disability progression independent of relapses (87%); a worsening of 2-points in any functional system (except the visual), even without changes in EDSS, suggests progression (80%), regardless of disease duration (> 20 years: 93%; 10-20 years: 87%) and age (87%). 20% time increase in T25-FW and 9HPT, together with an increase in EDSS score, are confirmatory of progression (87%). Panellists agreed to perform an annual cognitive exploration (80%), such as SDMT (100%), BRB-N (93%), BICAMS (93%). Experts agreed to evaluate QoL (80%), depression (73%) and fatigue (73%) once annually. A sustained change in brain atrophy suggests progression (80%) provided major physiological factors have been ruled-out (83%). Sustained medullary atrophy suggests progression (100%) but more precise techniques should be used to confirm a diagnosis (93.3%).

Conclusions

The overall consistency in the level of agreement in the different items is high and reinforces the results obtained. These areas of collective agreement could guide neurologists in anticipating progression and planning informed clinical and therapeutic interventions.

Collapse
Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0324 - Effect of ocrelizumab treatment in peripheral blood leukocyte subsets of Primary Progressive Multiple Sclerosis patients (ID 1613)

Abstract

Background

Ocrelizumab is the first drug approved as disease modifying treatment for primary progressive (PP) multiple sclerosis (MS). As a humanized monoclonal antibody targeting CD20 cells, it is widely known that ocrelizumab treatment results in B cells depletion, but less is known about the effects of this drug in other blood leukocyte subsets of PPMS patients.

Objectives

To explore the changes induced by ocrelizumab in blood immune cells of PPMS patients to further understand their effects in the abnormal inflammatory response.

Methods

Multi-centre prospective longitudinal study including fifty‐three PPMS patients who initiated ocrelizumab treatment. Effector, memory, and regulatory cells were analyzed by flow cytometry at baseline and after 6 months of treatment. To assess differences between baseline and after 6 months, Wilcoxon matched paired tests were used and p values were corrected using Bonferroni test.

Results

Ocrelizumab decreased numbers of naïve and memory B cells (p<0.0001) and those of B cells producing interleukin (IL)-6, IL-10, granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-alpha (p<0.0001 in all cases). A reduction of CD20+ T cell numbers (p=0.02) and percentages (p<0.0001) was also observed. We also detected a clear remodelation of the T cell compartment characterized by relative increases of the naïve/effector ratio in CD4+ (p=0.002) and CD8+ (p=0.002) T cells, and relative decreases of CD4+ (p=0.03) and CD8+ (p=0.004) T cells producing interferon-gamma. Total monocyte numbers increased (p=0.002), with no changes in those producing inflammatory cytokines. All these changes resulted in a reduction of serum neurofilament light chain (sNfL) levels (p=0.009).

Conclusions

Effector B cell depletion by ocrelizumab treatment induces changes in the T cell response of PPMS patients towards a low inflammatory profile. This resulted in a decrease of sNfL levels.

Collapse
Disease Modifying Therapies – Risk Management Poster Presentation

P0327 - Effectiveness and safety profile of the Natalizumab extended interval dosing in a Spanish cohort (ID 1815)

Presentation Number
P0327
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Previous Biogen analyses of the US TOUCH Registry showed that the risk of developing natalizumab-associated progressive multifocal leukoencephalopathy (PML) among anti-JCV antibody positive natalizumab-treated patients was significantly lower with extended interval dosing (EID) compared with standard interval dosing (SID). However, the efficacy of EID was not evaluated in these analyses. Real-world studies and modelling data suggest that a patient population stable on natalizumab SID who is then switched to EID is more likely to maintain efficacy with EID as compared to a population who initiates natalizumab on EID.

Objectives

The main objective of the study is to evaluate the effectiveness (measured by the annualized relapse rate - ARR) of natalizumab EID in subjects who have been previously treated with natalizumab SID during the 12-month list, in relation to continuous SID treatment.

Methods

Observational, open-label study with retrospective analysis of a prospective cohort of patients with relapsing-remitting multiple sclerosis (RRMS) treated at Hospital Ramón y Cajal (Madrid) with natalizumab for 12 months using SID (Infusion every month). All patients were transferred after a period of initial treatment at standard interval doses to a 6-week EID, according to hospital protocol, eliminating a potential selection bias for assigning less active patients to the EID group Demographic, clinical, radiological and immunological variables were collected.

Results

61 patients were included, 33 (54%) women, with a median (range) age at treatment initiation of 35 (17-55) years. Median (range) treatment duration was 5,2 years (2-11,3), 3,47 years (1,4-7,8) in SID, 1,7 years (0,5-4,1) in EID. There was no difference in ARR, mean [95% confidence interval (CI)], (SID: 0.05 [0,01-0,1]; EID: 0.02 [0,02-0,05]; P=0.558), or EDSS (SID: 2,35 [1,9-2,7], EID: 2,67 [2,2-3,9]; p=0,42).

Conclusions

This study does not demonstrate significant differences in relapse outcomes between SID and EID periods of patients who switched to EID from natalizumab after ≥1 year on SID. These results are consistent with previous analyzes without comparison that concluded that efficacy is maintained after switching to EID. Consistent MRI and EDSS results will be shown in the final poster. An ongoing prospective randomized trial of EID versus SID will provide a more complete understanding of the effectiveness of natalizumab EID.

Collapse
Imaging Poster Presentation

P0631 - Recommendations for the coordination of Neurology and Neuroradiology departments in the management of patients with multiple sclerosis (ID 314)

Abstract

Background

Magnetic resonance imaging (MRI) is widely used for the diagnosis and follow-up of patients with multiple sclerosis (MS). It is considered the most reliable and accurate paraclinical tool to evaluate disease activity and progression due to the high sensitivity to detect demyelinating lesions. Coordination between Neurology and Neuroradiology departments is essential to ensure that radiological studies are effectively performed and interpreted. However, in clinical practice, this coordination can be improved to maximize MS management and care.

Objectives

To establish a set of organizational recommendations focused on the coordination between neurologists and neuroradiologists to improve MS management in clinical practice.

Methods

A panel of 17 experts, including neurologists and neuroradiologists, from eight Spanish academic hospitals participated in the study. The Consensus Recommendation Guideline was conducted in four phases: 1) definition of the scope and methodology of the study; 2) review of the literature on good practices or recommendations in the use of MRI in MS; 3) discussion of drafted recommendations to achieve a consensus between the authors; 4) formalization and validation of the contents in a set of recommendations.

Results

We provide nine recommendations to improve the coordination between Neurology and Neuroradiology departments, which can be summarized as follows: 1) standardize the MRI requests, reports and schedules, 2) create shared protocols for MRI studies, 3) establish multidisciplinary working committees and coordination sessions, and 4) generate formal communication channels to improve the coordination between professionals from both departments. These recommendations are based on the available scientific evidence, international good practice guidelines and the experience of the panel experts.

Conclusions

We propose a series of recommendations expected to serve as a functional guide to implement improvements in the coordination between neurologists and neuroradiologists that will ultimately lead to improve the diagnosis and follow-up of MS patients.

Collapse
Pathogenesis – Immunology Poster Presentation

P0975 - Lipid-specific oligoclonal IgM bands condition age-related changes in multiple sclerosis (ID 1396)

Abstract

Background

Age has high influence on clinical course of chronic inflammatory diseases such as multiple sclerosis (MS). Lipid-specific oligoclonal IgM bands (LS-OCBM) in cerebrospinal fluid (CSF) of MS patients are biomarkers of high inflammatory disease. However, the relationship between both variables has not been fully studied.

Objectives

To explore age-related changes in CSF of MS patients leading to senescence and to study the role of LS-OCBM in this process.

Methods

A prospective cross-sectional study of 263 MS patients followed at Ramon y Cajal University Hospital, Madrid. Seventy-two showed (M+) and 191 (M-) lacked CSF LS-OCBM. We explored CSF immune cells, soluble mediators, microRNAs and clinical data.

Results

MS patients older than 45 years (O45) showed significant rises in CSF Programmed death ligand 1 (PD-L1; p=0.001) and T-cell immunoglobulin mucin-3 (TIM-3; p<0.0001), which induce lymphocyte tolerance, and in Chitinase 3-like-1 (p<0.0001) and Activin-A (p<0.0001), which lead to innate cell activation. This associated with low values of pro-inflammatory B cells and of Th17 lymphocytes. In addition, M- O45 patients experienced significant increases in miR-125b-5p (p=0.01) and miR-145-5p (p=0.02), two miRNA associated with immune senescence, an increase of let-7b-5p (p=0.01) that counteract innate-cell activation, a dramatic decrease of CSF lymphocytes (p<0.0001) and of NK cells (p=0.002) and increased serum anti-cytomegalovirus antibodies (p=0.009). However, M+ O45 patients exhibited a reduction of miR-204-5p (p=0.01), that induce innate-cell activation and increased CSF levels of superoxide dismutase (p=0.04) and isoprostane (p=0.03), markers of oxidative stress. These changes resulted in increased Multiple Sclerosis Severity Score (MSSS) on M+ O45 patients.

Conclusions

M- O45 MS patients showed inhibition of the intrathecal adaptive immune response and early immunosenescence. Conversely, M+ O45 MS patients displayed intrathecal innate cell activation and accelerated disability worsening. These data could be relevant for treating aged MS patients.

Collapse
Patient-Reported Outcomes and Quality of Life Poster Presentation

P1024 - Economic impact of the Secondary Progressive Multiple Sclerosis in Spain: Interim analysis of the DISCOVER study (ID 1595)

Abstract

Background

Multiple Sclerosis (MS) is a chronic, inflammatory, autoimmune, neurodegenerative disease. Around 19% of treated patients with relapsing-remitting MS progress to Secondary Progressive MS (SPMS) 15 years after disease onset, representing the most severe stage of the disease. MS symptoms lead to a general disability, impacting the quality of life of patients and also being related with an important economic burden on the National Health System, the patients, their caregivers and the whole society.

Objectives

There are limited published data on the economic impact of SPMS. The main objective of the study was to estimate the economic impact of SPMS in Spain.

Methods

DISCOVER (CBAF312AES01) is an observational, non-interventional, cross-sectional, retrospective and multicenter study, including 297 SPMS patients ≥18 years treated and monitored according to routine clinical practice in Spain in 34 public hospitals. All data was collected in one single visit. Primary endpoint: total annual cost per patient, including direct healthcare and non-healthcare costs and indirect costs. Interim results from 99 patients are presented.

Results

62.6% females; mean (SD) age 53.1 (9.3) years; 40.4% with higher education; 86.9% living with a relative. Mean (SD) time since first MS diagnosis was 17.5 (8.9) years and since progression to SPMS 5.2 (4.3) years. At diagnosis, mean (SD) EDSS was 2.0 (1.1), being 5.0 (1.1) at the time of progression and 5.9 (0.8) at the study visit, 47.5% patients reaching EDSS>6. 12.8% of patients presented relapses between 12-24 months before the study. According to EQ-5D-5L, mean (SD) utility (<1) was 0.48 (0.27) for patients with Gd+ lesions and/or relapses 2 years before. According to EQ-5D-5L, mean (SD) utility (<1) for patients with cognitive impairment was 0.45 (0.29) vs 0.51 (0.21) for those without it. Mean (SD) utility for Spanish general population was 0.897 (0.21). EDSS score showed a significative effect (P=0.0074) on the economic burden of the disease, with total costs increasing from 14,546€ (EDSS 4-4.5) to 21,918€ (EDSS 5-5.5) and 26,832€ (EDSS=6). Costs related to patients with EDSS=6 from the societal, patient and healthcare system were 6,441€, 8,450€ and 11,941€, respectively.

Conclusions

Interim results of the DISCOVER study revealed a significant economic impact of MS progression, highlighting the importance of implementing therapeutic strategies specific to the SPMS patient within the early stages of progression.

Collapse
Patient-Reported Outcomes and Quality of Life Poster Presentation

P1050 - Quantifying the patient´s perspective in neuromyelitis optica spectrum disorders: Design of a multicenter, non-interventional study (ID 222)

Abstract

Background

Patients with neuromyelitis optica spectrum disorders (NMOSD) experience a spectrum of symptoms negatively impacting on daily living and quality of life. The systematic assessment of patient perspectives has the capacity to provide crucial clinical information that could otherwise be lost when relying on clinical evaluation alone. However, the patient experience living with NMOSD is limited, in particular implementing standardized patient-reported outcomes (PROs).

Objectives

The primary objective of this study protocol is to assess the health-related quality of life and well-being of NMOSD patients.

Methods

A multicenter, non-interventional, cross-sectional study will be conducted with patients diagnosed with NMOSD (2015 Wingerchuk criteria) (PERSPECTIVES-NMO Study). Primary outcomes measures will be the 29-item Multiple Sclerosis Impact Scale and the Satisfaction with Life Scale. Demographic characteristics, clinical and imaging outcomes will be collected, including the number and type of attacks, antibody status, Expanded Disability Status Scale score, Nine-Hole Peg Test, Timed 25-Foot Walk, and Magnetic Resonance Imaging findings. Cognition will be evaluated using the Rao Brief Repeatable Neuropsychological Battery. Additional outcomes from the patient´s perspective (PROs) will be collected, including symptoms severity (SymptoMScreen questionnaire), fatigue (Fatigue Impact Scale for Daily Use), pain (MOS Pain Effects Scale), mood (Beck Depression Inventory-Fast Screen), perception of stigma (8-item Stigma Scale for Chronic Illness), and work-related difficulties (23-item Multiple Sclerosis Work Difficulties Questionnaire).

Results

Patient recruitment began in December 2019 with a planned total sample of 70 patients. The study is currently ongoing.

Conclusions

The study results are expected to provide meaningful insights into the clinical burden of disease. A better understanding of patient experiences may foster the development of patient-centered specific plans and more targeted rehabilitation in clinical practice.

Collapse