FLENI

Author Of 7 Presentations

Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0408 - Therapeutic Plasma Exchange in MS relapses: long term outcome (ID 1415)

Speakers
Presentation Number
P0408
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

High-dose short-term intravenous methylprednisolone (IVMP) is the standard treatment for Multiple Sclerosis (MS) relapses. However, 25% of patients do not respond and remain with significant disability. In these patients, therapeutic plasma exchange (TPE) has proven effective, although evidence of long-term efficacy after use of this procedure is lacking.

Objectives

The aims of this study were to: 1) compare outcomes of patients treated with or without TPE at 12, 18 and 24 months, and 2) evaluate features associated with better response to TPE.

Methods

We performed a retrospective cohort study of all relapse remitting MS patients (RRMSp) treated with IVMP and TPE between January 2011 and January 2018 and compared them to a second group of RRMSp, matched for age, sex, disease duration and disability level at time of relapse, treated only with IVMPS. Number of relapses were recorded. Good response to treatment was defined as at least 50% reduction in EDSS score. Results were reported as median and interquartile range for numerical variables, and as percentage of the total number of patients, for categorical variables. P values below 0.05 were considered significant.

Results

Twenty-four patients (66% female, age: 39± 11 years) treated with TPE, and 43 patients treated with IVMP alone (70% female, age: 39± 6 years) were included. TPE-treated patients had experienced more relapses in the 2-years prior to the study (3±2 vs 2±1, p=0,03). Time from symptom onset to treatment with IVMP or duration of IVMP treatment was similar in both groups (5 ± 9 days vs 7± 11 days, p=0.1). After the relapse, TPE-treated patients were escalated to a high efficacy disease modifying therapy more frequently during follow up than the comparator group (25% vs 16%, p=0,02).

Although initial EDSS scores were similar in both groups, no differences were found in EDSS or Kurtzke functional systems scores at 12, 18 and 24-months follow-up (TPE 1 (0-2) vs IVMP 1 (0-2)).

65% of RRMSp treated with TPE had a good response to treatment. No significant association was found between positive response and initial relapse severity, distribution or number of gadolinium-enhancing lesions, or time to TPE.

Conclusions

No differences in functional outcomes were found in MS relapses treated with or without TPE after 24 months follow up; nor were any predictors of favorable response to treatment with TPE in this preliminary analysis.

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Epidemiology Poster Presentation

P0427 - Absence of latitudinal gradient in oligoclonal bands prevalence in Argentina (ID 858)

Abstract

Background

Similarly, to what occurs with MS prevalence, it has been previously described that oligoclonal bands (OCB) prevalence follows a latitudinal gradient being more frequent farther away from the equator. Argentina has the particularity of being longitudinally extensive (21°46’S to 66°13’S). Previous epidemiological studies from Argentina have not found an MS prevalence latitudinal gradient.

Objectives

The aim of the present study is to describe the prevalence of OCB in CSF in patients with MS, CIS and RIS included in the Argentinean MS and NMOSD registry (RelevarEM, NCT 03375177) and to investigate if the prevalence follows a latitudinal gradient.

Methods

RelevarEM is a longitudinal, observational MS and NMOSD registry in Argentina. For each province, an average latitude was calculated using extreme N and S latitudes obtained from Google Maps. Regarding OCB, pattern II or III where considered as positive. The frequency of OCB was calculated for each diagnostic category (MS, CIS, RIS) and for each province. Statistical analysis was carried out using SPSS v22. Multivariate logistical regression analysis was performed considering OCB as a dichotomic dependent variable and latitude as an ordinal independent variable, adjusted by clinically relevant variables. Also, the percentage of patients OCB positive for each province was calculated and linear correlation was tested.

Results

We included 2866 patients from different locations in Argentina (92.4% MS, 5.8% CIS and 1.8% RIS). The mean age at diagnosis (SD) was 32.7 (11.2), 35.2 (10.7) and 40.7 (11.2) for MS, CIS and RIS patients, respectively. Lumbar puncture was performed in 54.6%, 63.9%, and 43.4% of MS, CIS and RIS patients, respectively. OCB where positive in 75.4%, 55.7% and 60.9% of MS, CIS and RIS patients, respectively. No association was found between OCB positivity and latitude, adjusted by gender, age at diagnosis and diagnostic category. No linear correlation was found between the percentage of OCB positive patients and latitude.

Conclusions

Similarly, to what has been described regarding MS prevalence, OCB positivity does not seem to follow a latitudinal gradient in Argentina. Also, OCB positivity in our study is lower that described in previous reports from other world regions.

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Comorbidities Poster Presentation

P0483 - Prevalence of cancer in multiple sclerosis patients in Argentina: cross sectional study from RelevarEM (ID 1043)

Abstract

Background

Multiple Sclerosis (MS) is an autoimmune demyelinating and neurodegenerative disease of the central nervous system of multifactorial origin. Studies about the prevalence of cancer in MS population are scarce and results are conflicting. Previous studies described a higher prevalence as well as an increased risk of cancer in MS patients while there are others that found no differences regarding general population.

Objectives

The aim of our study was to estimate the prevalence of cancer in a large sample of multiple sclerosis patients in Argentina.

Methods

the eligible study population and cohort selection included all patients with definite MS included in the Argentinean MS and NMOSD registry (RelevarEM, NCT 03375177) at 31 December 2019. History of current or past cancer diagnosis, was collected. Prevalence rates and 95% CI were calculated.

Results

We analyzed 2647 MS patients. 14 malignancies were identified. Overall prevalence of cancer was 0.53% (CI95% 0.02-0.08%). 78.6% were female, 85.8% relapsing remitting MS, median (IQR) disease duration: 10.5 (6-13) years; median (IQR) age at diagnosis: 42.5 (37-49); median (IQR) age at study date: 52.5, median (IQR); current EDSS: 2 (1.5-4.5); 42% patients were untreated and 58% under DMT (beta interferon 1a: 14.3%, 1b: 7.1%, glatiramer acetate: 7.1% and fingolimod: 28.6%). Most frequent malignancy was breast cancer (28.6%).

Conclusions

The prevalence of cancer in MS population identified in Argentina was 0.53% (CI 95% 0.02-0.08), being females more affected than males and breast cancer the most frequent one.

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Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0720 - Incidence of relapses in NMOSD patients under immunosupressive therapies in Argentina: observational study from RelevarEM. (ID 1684)

Abstract

Background

Several retrospective studies have demonstrated the clinical benefits of immunosuppressive therapies (IST) such as azathioprine (AZA), mycophenolate mofetil (MMF) and rituximab (RTX) for reducing relapse rates in neuromyelitis optica spectrum disorders (NMOSD) patients. However, there is considerable uncertainty regarding the relative benefits and harms associated with each of these IST in real world clinical practice and current data describing the strategies are limited

Objectives

The objective of this study was to describe the incidence of relapses in patients with NMOSD under IST included in the Argentinean MS and NMOSD registry (RelevarEM, NCT 03375177).

Methods

We conducted a retrospective cohort study from RelevarEM. RelevarEM is a longitudinal, strictly observational MS and NMOSD registry in Argentina. From May 2018 to June 2020, the centers and principal investigators were contacted, and patients were incorporated into the Registry. NMOSD patients were defined based on the 2015 International Consensus Diagnostic Criteria for NMOSD. Relapses during the study period, demographics and radiological (e.g. new/enlarging and/or enhancing-contrast MRI lesions) data were collected. Only patients under IST were included in the analysis. Patients contributed person-years of follow-up for the study period. Incidence rates and 95% CI were calculated. Thus, global and associated with each IST incidence density rate of relapses was estimated.

Results

We included a total of 132 (77% women) NMOSD patients with a median age at diagnosis of 36 years (27-47) and a disease duration of 6 years (4-10). Aquaporin-4 antibody was positive in 54.8%. At the time of entering the registry, 39.4% were treated with RTX, 33.3% with AZA, 3.6% MMF. The global incidence density rate of relapse was 0.032/person-year (CI95% 0,021-0,048), for RTX 0.051 (CI95% 0,024-0,1) and for AZA 0,031 (CI95% 0,016-0,06). There were no relapses in the group of MMF during this period of time.

Conclusions

This study showed a low incidence density rate of relapses in NMOSD patients under IST during this study period. Further studies will help expand our initial findings, hopefully leading to improve treatment options for NMOSD patients.

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Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0762 - What percentage of AQP4-Ab-negative NMOSD patients are MOG-Ab positive? A study from the Argentinean multiple sclerosis registry (RelevarEM) (ID 1033)

Abstract

Background

Myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) have been described in aquaporin-4-antibodies(AQP4-Ab)-negative neuromyelitis optica spectrum disorders (NMOSD) patients.

Objectives

We aimed to investigate the percentage of AQP4-Ab-negative NMOSD patients who are positive for MOG-Ab included in the Argentinean MS and NMOSD registry (RelevarEM, NCT 03375177).

Methods

RelevarEM is a longitudinal, strictly observational multiple sclerosis (MS) and NMOSD registry in Argentina. Epidemiological, serological test and neuroimaging (MRI) data from NMOSD were described.

Results

A total of 165 patients (79 AQP4-Ab positive, 67 AQP4-Ab negative and 19 unknown) were included. Of these, 155 patients fulfilled the 2015 NMOSD diagnostic criteria. Of 67 AQP4-Ab-negative patients, 36 were tested for MOG-Ab and 10 of them (31.8%) tested positive. Presence of relapses during the previous 6 months (40% vs. 12.9%), shorter disease duration (3.9 vs. 7.5 years), lower disability (2.3 vs. 3.4) and treatment duration (1.5 vs. 3.4 years) and both optic neuritis (90% vs. 44.5%) and optic nerve lesion on MRI (80% vs. 25.1%) were significantly associated with MOG-Ab-positive compared with NMOSD respectively

Conclusions

This is the first study of the longitudinal Argentinean registry of MS and NMOSD describing and comparing diseases that contributes to provide reliable real-world data in the country. We observed that 31.8% (10/36) of the AQP4-ab-negative patients tested for MOG-Ab were positive for this antibody, in line with results from other world regions.

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Observational Studies Poster Presentation

P0836 - Aggressive multiple sclerosis in Argentina: data from the nationwide registry RelevarEM (ID 1632)

Abstract

Background

Aggressive MS (AMS) describes a form of the disease with a rapid progressive course leading to significant disability in multiple neurologic systems or even death in a relatively short time after onset. Despite there being no consensus on the exact definition of AMS, several studies performed during the last years have tried to better identify and understand the frequency and distribution as well as the progression and treatment response in order to determine more accurately which patients with AMS would most benefit from higher-efficacy, higher-risk treatments

Objectives

The objectives of the present study were to describe the frequency of aggressive multiple sclerosis (AMS) as well as to compare clinical and radiological characteristics in AMS and non-AMS patients included in the Argentinean MS and NMOSD registry (RelevarEM, NCT 03375177).

Methods

The eligible study population and cohort selection included adult-onset patients (≥18 years) with definite MS. AMS were defined as those reaching confirmed EDSS ≥6 within 5 years from symptom onset. Confirmation was achieved when a subsequent EDSS ≥6 was recorded at least six months later but within 5 years of the first clinical presentation. AMS and non-AMS were compared using the χ2 test for categorical and the Mann-Whitney for continuous variables at MS onset and multivariable analysis was performed using forward stepwise logistic regression with baseline characteristics at disease onset.

Results

A total of 2158 patients with MS were included: 74 AMS and 2084 non-AMS. The prevalence of AMS in our cohort was 3.4% (95%CI 2.7-4.2). AMS were more likely to be male (p=0.003), older at MS onset (p<0.001), have primary progressive MS (PPMS) phenotype (p=0.03), multifocal presentation (p<0.001), and spinal cord as well as infratentorial lesions at MRI during disease onset (p=0.004 and p=0.002, respectively).

Conclusions

3.4% of our patient population could be considered AMS. Men, patients older at symptom onset, multifocal presentation, PPMS phenotype, and spinal cord as well as brainstem lesion on MRI at clinical presentation all had higher odds of having AMS.

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Pathogenesis – Immunology Poster Presentation

P0985 - Obesity and Multiple Sclerosis risk. The role of Leptin (ID 1008)

Speakers
Presentation Number
P0985
Presentation Topic
Pathogenesis – Immunology

Abstract

Background

Obesity in childhood and in adolescence increases the risk of MS by inducing a chronic low-grade inflammatory state, characterized by altered secretion of adipokines, of which leptin is the best characterized.

Objectives

The main goal of this study was to investigate the effects of leptin on different T cell populations, in order to gain more insight into the link between leptin and obesity.

Methods

Three hundred and nine RRMS patients and 322 matched controls were invited to participate in a cross-sectional survey, to confirm whether excess weight/obesity in adolescence or early adulthood were associated with increased risk of MS.

Serum leptin levels were determined by ELISA. MBP83-102, and MOG63-87 peptide-specific T cells lines were expanded from peripheral blood mononuclear cells. Leptin receptor, p-STAT3, pERK1/2, and p27kip1 expression were assayed using RT-PCR. Apoptosis induction was determined by Annexin V detection. Cytokines were assessed by ELISPOT and ELISA, and regulatory T cells (Treg cells) detected by flow cytometry.

Results

Logistic regression analysis, with smoking as covariate, showed excess weight at age 15 and obesity at age 20 increased the risk of developing MS (OR=2.16, p=0.01 and OR=3.89, p=0.009). Leptin levels correlated with BMI(r=0.88, p<0.0001) in both groups. Addition of Leptin to cultures increased proliferation of autoreactive T cells, reduced apoptosis induction, and promoted pro-inflammatory cytokines secretion (p values < 0.001). Obese patients produced higher numbers of pro- inflammatory cytokines-secreting cells compared to overweight/normal/underweight subjects (p<0.001).

Inverse correlation was found between leptin levels and circulating CD4+CD25+ Treg cells (r=-0.97, p<0.0001). Leptin also inhibited Treg cell proliferation, inducing hypo-responsiveness. Effects of leptin on autoreactive T cells were mediated by increased STAT3 and ERK1/2 phosphorylation and down modulation of the cell cycle inhibitor P27kip1. By contrast, leptin effects on Treg cells were mediated by decreased phosphorylation of ERK1/2 and upregulation of p27kip1.

Conclusions

Leptin has a dual effect on T cell modulation. On one hand it promotes proliferation of autoreactive T cells, secretion of pro-inflammatory cytokines, and exerts an anti-apoptotic action. On the other, leptin inhibits Treg cell proliferation, inducing hypo-responsiveness, mediated by the opposite effects of STAT3, ERK1/2 phosphorylation, and p27kip1 expression.

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Presenter Of 2 Presentations

Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0408 - Therapeutic Plasma Exchange in MS relapses: long term outcome (ID 1415)

Speakers
Presentation Number
P0408
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

High-dose short-term intravenous methylprednisolone (IVMP) is the standard treatment for Multiple Sclerosis (MS) relapses. However, 25% of patients do not respond and remain with significant disability. In these patients, therapeutic plasma exchange (TPE) has proven effective, although evidence of long-term efficacy after use of this procedure is lacking.

Objectives

The aims of this study were to: 1) compare outcomes of patients treated with or without TPE at 12, 18 and 24 months, and 2) evaluate features associated with better response to TPE.

Methods

We performed a retrospective cohort study of all relapse remitting MS patients (RRMSp) treated with IVMP and TPE between January 2011 and January 2018 and compared them to a second group of RRMSp, matched for age, sex, disease duration and disability level at time of relapse, treated only with IVMPS. Number of relapses were recorded. Good response to treatment was defined as at least 50% reduction in EDSS score. Results were reported as median and interquartile range for numerical variables, and as percentage of the total number of patients, for categorical variables. P values below 0.05 were considered significant.

Results

Twenty-four patients (66% female, age: 39± 11 years) treated with TPE, and 43 patients treated with IVMP alone (70% female, age: 39± 6 years) were included. TPE-treated patients had experienced more relapses in the 2-years prior to the study (3±2 vs 2±1, p=0,03). Time from symptom onset to treatment with IVMP or duration of IVMP treatment was similar in both groups (5 ± 9 days vs 7± 11 days, p=0.1). After the relapse, TPE-treated patients were escalated to a high efficacy disease modifying therapy more frequently during follow up than the comparator group (25% vs 16%, p=0,02).

Although initial EDSS scores were similar in both groups, no differences were found in EDSS or Kurtzke functional systems scores at 12, 18 and 24-months follow-up (TPE 1 (0-2) vs IVMP 1 (0-2)).

65% of RRMSp treated with TPE had a good response to treatment. No significant association was found between positive response and initial relapse severity, distribution or number of gadolinium-enhancing lesions, or time to TPE.

Conclusions

No differences in functional outcomes were found in MS relapses treated with or without TPE after 24 months follow up; nor were any predictors of favorable response to treatment with TPE in this preliminary analysis.

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Pathogenesis – Immunology Poster Presentation

P0985 - Obesity and Multiple Sclerosis risk. The role of Leptin (ID 1008)

Speakers
Presentation Number
P0985
Presentation Topic
Pathogenesis – Immunology

Abstract

Background

Obesity in childhood and in adolescence increases the risk of MS by inducing a chronic low-grade inflammatory state, characterized by altered secretion of adipokines, of which leptin is the best characterized.

Objectives

The main goal of this study was to investigate the effects of leptin on different T cell populations, in order to gain more insight into the link between leptin and obesity.

Methods

Three hundred and nine RRMS patients and 322 matched controls were invited to participate in a cross-sectional survey, to confirm whether excess weight/obesity in adolescence or early adulthood were associated with increased risk of MS.

Serum leptin levels were determined by ELISA. MBP83-102, and MOG63-87 peptide-specific T cells lines were expanded from peripheral blood mononuclear cells. Leptin receptor, p-STAT3, pERK1/2, and p27kip1 expression were assayed using RT-PCR. Apoptosis induction was determined by Annexin V detection. Cytokines were assessed by ELISPOT and ELISA, and regulatory T cells (Treg cells) detected by flow cytometry.

Results

Logistic regression analysis, with smoking as covariate, showed excess weight at age 15 and obesity at age 20 increased the risk of developing MS (OR=2.16, p=0.01 and OR=3.89, p=0.009). Leptin levels correlated with BMI(r=0.88, p<0.0001) in both groups. Addition of Leptin to cultures increased proliferation of autoreactive T cells, reduced apoptosis induction, and promoted pro-inflammatory cytokines secretion (p values < 0.001). Obese patients produced higher numbers of pro- inflammatory cytokines-secreting cells compared to overweight/normal/underweight subjects (p<0.001).

Inverse correlation was found between leptin levels and circulating CD4+CD25+ Treg cells (r=-0.97, p<0.0001). Leptin also inhibited Treg cell proliferation, inducing hypo-responsiveness. Effects of leptin on autoreactive T cells were mediated by increased STAT3 and ERK1/2 phosphorylation and down modulation of the cell cycle inhibitor P27kip1. By contrast, leptin effects on Treg cells were mediated by decreased phosphorylation of ERK1/2 and upregulation of p27kip1.

Conclusions

Leptin has a dual effect on T cell modulation. On one hand it promotes proliferation of autoreactive T cells, secretion of pro-inflammatory cytokines, and exerts an anti-apoptotic action. On the other, leptin inhibits Treg cell proliferation, inducing hypo-responsiveness, mediated by the opposite effects of STAT3, ERK1/2 phosphorylation, and p27kip1 expression.

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