University of Genoa

Author Of 2 Presentations

Observational Studies Oral Presentation

PS01.04 - Comparison of disability trajectories in relapsing Multiple Sclerosis patients treated with early intensive or escalation treatment strategies

Abstract

Background

to date, no consensus exists on how aggressively and timely treat relapsing-remitting multiple sclerosis (RRMS) patients.

Objectives

To evaluate disability trajectories in a cohort of RRMS patients stratified according to two different disease modifying therapy (DMT) strategies, early intensive treatment (EIT) or moderate-efficacy treatment followed by escalation to higher-efficacy DMT (ESC).

Methods

RRMS patients with ≥5-year follow-up and ≥3 visits after start DMT, and a first visit within 3 years from disease onset were selected from the Italian MS Registry. EIT group included patients who received, as first DMT, fingolimod, natalizumab, mitoxantrone, alemtuzumab, ocrelizumab, cladribine. ESC group included those who received the high efficacy DMT after ≥1 year of glatiramer acetate, interferons, azathioprine, teriflunomide or dimethylfumarate treatment. Patients were 1:1 propensity score(PS)-matched for characteristics at the first DMT. The follow-up time from the first DMT start has been segmented into 12-month periods. The disability trajectories were evaluated by applying a longitudinal model for repeated measures with an autoregressive variance-covariance structure. The effect of early versus late start of high-efficacy DMT was assessed by the mean annual EDSS changes compared to baseline values (delta-EDSS) in EIT and ESC groups.

Results

The study cohort included 2,652 RRMS patients from 62 Italian MS centers. The PS matching procedure produced 365 pairs. The median (IQR) follow-up after the first DMT start was 8.5 (6.5–11.7) years. All of the ESC patients escalated to a higher-efficacy DMT after a median time of 5.1 (3.1–8.4) years. The estimated baseline EDSS with relative confidence interval (95% CI) value was 2.52 (2.33-2.71) in the ESC group and 2.45 (2.26-2.64) in the EIT group. Mean delta-EDSS at each 12 month period were all significantly (p<0.02) higher in the ESC group compared to the EIT group. In particular, the mean delta-EDSS differences between the two groups tend to increase from 0.1 (0.01-0.19, p=0.03) at 1 year to 0.30 (0.07-0.53, p=0.009) at 5 years and to 0.67 (0.31-1.03, p=0.0003) at 10 years.

Conclusions

Our results indicate that EIT strategy is more effective than ESC strategy in controlling disability progression and the effect tends to increase over time despite patients in the ESC group escalated to a higher-efficacy DMT.

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Observational Studies Oral Presentation

PS05.03 - Disease modifying treatment may delay time to wheelchair in primary progressive multiple sclerosis: a real-life cohort

Abstract

Background

Background: Except for ocrelizumab, treatment options in primary progressive multiple sclerosis (PPMS) are lacking, as randomized clinical trials failed to show efficacy in reducing disability progression in this patient population.

Objectives

Objective: To investigate the effectiveness of disease-modifying treatment (DMT) on hard disability outcomes (EDSS 6 and 7) in a real-life population of PPMS patients.

Methods

Methods: Using the Italian MS Registry, we selected PPMS patients with at least three EDSS evaluations and three years of follow-up. Study baseline was defined as the first EDSS evaluation for untreated patients and the date of the first DMT initiation for treated patients. The impact of DMT on the risk of reaching EDSS 6 and 7 was assessed as a dichotomous variable (yes versus no) and as a time-dependent covariate through multivariable Cox regression models (adjusted for age at baseline, sex, first EDSS score, symptoms at onset, annualized visit rate, annualized relapse rate). We compared outcomes with an as-treated analysis and used propensity-score matching (PSM) to select cohorts with comparable baseline characteristics. DMT-exposure was also evaluated in terms of quartiles of exposure.

Results

Results: Of the 1214 patients we included 671 females, mean ± Standard Deviation baseline age 48.7 ± 11.1 years, mean EDSS score 4.1 ± 1.8, 790 (65%) received a DMT during the follow-up (57% platform and 43% highly active treatments). In the whole sample, after a mean follow-up of 11.6 ± 6.3 years, 994 (82%) patients reached EDSS 6 and 539 (44%) EDSS 7. In the multivariable Cox regression models, the use of DMT analyzed as a dichotomous variable did not influence the risk of reaching EDSS 6 (aHR=1.1, 95% CI 0.95-1.28, p=0.181) and EDSS 7 (aHR = 0.93, 95% CI 0.77-1.12. p = 0.454). However, longer DMT exposure significantly reduced the risk of reaching EDSS 7 (aHR = 0.73, 95% CI 0.56-0.95, p =0.021). Of note, patients in the upper quartile of DMT exposure compared with those with shorter DMT exposure were younger at baseline (mean age 44.1 ± 10.6 years; p < 0.001) and received the first DMT closer to the disease onset (mean time to first DMT 6.8 years ± 6.1 ; p=0.002). All these findings were confirmed in the PSM analysis.

Conclusions

Conclusion: Our results suggest that longer exposure to DMT may delay time to wheelchair in PPMS patients. Moreover, treating younger patients and reducing the delay to treatment initiation may improve the patients’ long-term disability outcomes. To optimize treatment decision-making in PPMS further profiling of the best candidates to treatment is needed.

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Author Of 14 Presentations

Neuropsychology and Cognition Poster Presentation

LB1158 - COVID-19 pandemic and mental distress in Multiple Sclerosis: implications for clinical management (ID 1300)

Abstract

Background

in multiple sclerosis (MS), disease-related factors and dysfunctional coping might favour the development of mental distress induced by COVID-19 containment measures.

Objectives

to explore the relationship between mental distress, disability and coping strategies in the Italian MS population under lockdown.

Methods

Structural equation modeling (SEM) was applied to information collected via web-survey to identify modifiable factors that could account for mental distress. Information about the following domains was collected: (1) socio-demographic features; (2) general and MS related health status; (3) changes in lifestyle; (4) COVID-19 infection and risk perception; (5) physical disability assessed via the Patient-Determined Disease Steps (PDDS) scale and the Upper Extremity Function – Short Form (UEF) from the Quality of Life in Neurological Disorders (Neuro-QoL) measurement system; (6) cognitive function investigated using the Cognition Function– Short Form from the Neuro-QoL. Abstract reasoning, logical thinking and, in part, sustained attention, were measured using six Raven-like matrices; (7) mental distress: four domains from the Neuro-QoL were explored. Specifically, sleep disturbances, anxiety feelings, depressive symptoms, emotional dyscontrol; (8) coping strategies: individual response to lockdown was assessed using 18 items from the COPE-NVI-25, evaluating five independent coping strategies: avoidance (AV), social support (SS), positive attitude (PA), problem solving (PS) and turning to religion (TR).

Results

845 subjects (497 MS and 348 controls) were included in the study. MS patients showed higher scores than controls for depression (p=0.005), but not for anxiety, emotional dyscontrol or sleep disturbances. The SEM explained 74% of the variance observed in depression score. Within the model, three latent factors were characterized from measured variables: motor disability and cognitive dysfunction contributed to disability (β=0.509 and β=0.836, p<0.001); positive attitude and exercise contributed to active attitude (β=0.386 and β=0.297, p<0.001); avoidance, social support and watching TV contributed to passive attitude (β=0.301, β=0.243 and β=0.212, p<0.001). As per the relationship between latent factors and their influence on depression, disability contributed to passive attitude (β=0.855, p<0.001) while both passive and active attitude significantly influenced depression (β=0.729 and β=-0.456, p<0.001).

Conclusions

As practical implication of our model, favoring exercise would enhance active attitude and its positive impact on mental well-being while, at the same time, reducing the negative impact of disability on depression, representing a valuable tool for the long term management of COVID-19 related mental distress in MS.

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Neuropsychology and Cognition Poster Presentation

LB1171 - Embracing resilience in Multiple Sclerosis: a new perspective from COVID-19 pandemic. (ID 1742)

Speakers
Presentation Number
LB1171
Presentation Topic
Neuropsychology and Cognition

Abstract

Background

Coronavirus Disease 2019 (COVID-19), a severe acute respiratory syndrome due to Coronavirus 2 (SARS-CoV-2) infection, determined cross-sectional social and emotive consequences, representing an unprecedented social experiment. Past epidemiological experiences and recent studies dealing with COVID-19 pandemic and healthy population already showed the deep albeit heterogeneous psychological repercussions of pandemics. Nevertheless, little is known about the relationship between COVID-19 outbreak and patients with chronic diseases, Multiple Sclerosis (MS) in particular, and about the possible strategies for boosting resilience, a well-known protective and buffering instrument helping in facing the challenges of life.

Objectives

To assess the changes in mental distress during COVID-19 outbreak in patients with MS (pw-MS) and to identify predictive factors that could help in developing resilience and facing COVID-19 pandemic.

Methods

We enrolled 106 pw-MS (69 relapsing-remitting, 20 secondary-progressive and 17 primary-progressive) who had undergone neuropsychological assessment before outbreak (between January the 1st 2019 and March the 1st 2020): patients were previously tested with Brief International Cognitive Assessment for MS (BICAMS), Hospital Anxiety and Depression Scale (HADS) and patient-reported MS Neuropsychological Screening Questionnaire (MSNQ-P). All patients were asked to fulfill an online survey comprehensive of sociodemographic information (e.g. marital and employment status), HADS self-rating Scale, MSNQ-P Questionnaire and finally Connor-Davidson Resilience self-rating Scale (CD-RISC 25), in order to evaluate resilience. Statistical analyses (repeated-measures ANCOVA) were performed using SPSS 23.

Results

Even if no significant changes in HADS and MSNQ-P scores were detected during COVID-19 pandemic in our population, pre-existing lower HADS and MSNQ-P scores were found to be significantly (p<0.0001) and independently associated with a better resilience attitude; conversely, no demographic, disease- and treatment-related elements resulted predictive neither of anxiety, depression and perceived cognitive status nor of better resilient behaviour

Conclusions

Our study confirms the fundamental role of anxiety diagnosis and of neuropsychological evaluation in pw-MS, outlining its compelling role in predicting a resilient and positive response in case of pervasive commitment and the necessity of a comprehensive care for pw-MS.

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Clinical Outcome Measures Poster Presentation

P0124 - Ocrelizumab treatment in patients with relapsing-remitting multiple sclerosis: a single-center real-world experience (ID 1619)

Speakers
Presentation Number
P0124
Presentation Topic
Clinical Outcome Measures

Abstract

Background

ocrelizumab (OCR) treatment in pivotal trials of patients (pts) with relapsing-remitting multiple sclerosis (RRMS) was associated with high clinical efficacy and safety. However, real word data on efficacy and safety are still scarce

Objectives

To provide first experience on patients with RRMS treated with OCR in a single center real-world setting (MS Center of University of Genoa)

Methods

We collected safety and efficacy data from pts with RRMS treated with OCR. The probability of disability worsening-free survival, relapse-free survival, MRI-activity free-survival and NEDA-3 status was calculated with the Kaplan-Meier estimator and Cox proportional hazards regression analysis.

Results

96 RRMS pts [60 females (62.5%), mean (SD) age 37.3 (10.2) years] with a mean disease duration (DD) of 9.6 (9.3) years, a median (IQR) baseline EDSS of 2.5 (2-4) and a mean ARR of 0.79 (0.73). Median (IQR) number of previous DMTs was 1 (0-2). The mean time from previous DMT discontinuation and OCR start of 209 (661) days. Reasons for previous DMTs discontinuation were (i) lack of efficacy for 45 (67%), (ii) occurrence of adverse events for 7 (10%) and (iii) high JCV titer during natalizumab treatment for 5 (7.5%) pts. 28 pts (29.5%) had not received any DMT prior to OCR. Naïve pts had significantly shorter disease duration (2.6 vs 12.5 years; p<0.0001), had higher ARR (1.1 vs 0.7; p=0.002) and more frequently exhibited inflammatory activity on baseline MRI scan (96.3% vs 74.6%; p=0.019). Mean follow-up (FU) was 1.4 (1.2) years.

At 1-year FU, MRI-inflammatory activity free survival was 75.9%, relapse free survival was 95.9%, progression free survival was 98.7%. 2-years NEDA-3 status was achieved in 73.6% of pts. At multivariate analyses, adjusting for DD, ARR and baseline MRI activity, 2-years NEDA-3 status was significantly higher in naïve compared with treated pts [90.7% versus 60.8% at the end of the observation period; HR (CI 95% ) 0.14 (0.03-0.65); p=0.012]. We recorded 55 adverse events in 39 pts (4 lower respiratory tract infections; 18 upper respiratory tract infections; 7 herpes simplex-1 reactivation; 1 shingles; 8 upper urinary tract infections; 2 breast cancers). No serious infusion-associated reactions were reported

Conclusions

OCR treatment allows complete disease control in a high proportion of real-world RRMS pts, with a manageable safety profile. Although ocrelizumab can control disease activity after failure of highly efficacy DMTs, its efficacy seems to be higher in naïve patients

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Clinical Outcome Measures Poster Presentation

P0161 - Short-term evaluation of alemtuzumab to ocrelizumab switch in MS patients with disease activity after alemtuzumab: an Italian multicentric study. (ID 1603)

Speakers
Presentation Number
P0161
Presentation Topic
Clinical Outcome Measures

Abstract

Background

the management of MS patients (pts) who show disease activity after 2 alemtuzumab (ALM) courses represents an unsolved issue. No real-life data about the switch to ocrelizumab (OCR) have been reported yet.

Objectives

To describe efficacy and safety outcome of OCR patients switching from ALM due to persistence of disease activity after ALM

Methods

MS pts who switched from ALM to OCR from March 2019 to March 2020 were retro- and prospectively recruited from different Italian MS Centers. Clinical, immunological and neuroradiological data about ALM treatment period, ALM-OCR interval and OCR treatment period were collected.

Results

we recruited 23 MS pts [mean age: 35.7(SD±6.8); female, 40.1%; Relapsing Remitting, (RR): 75.8%, active Secondary progressive, (aSP): 24.2%; mean time interval (days) from II ALM course: 87.4(SD±108); cumulative number of relapses: 21; mean number of new T2 and Gd+ lesions: 4.1(SD±4.5) and 1.6(SD±3.1); median EDSS:3(range 1-7)]. The mean follow-up (FU) from OCR start was 7.9±7.4 months. Efficacy: 4 (17.4%) pts had a relapse after OCR start (1 pt relapsed between the first and the second OCR infusion and 3 pts after 3, 11 and 15 months from OCR start respectively), with complete recovery after steroid treatment. 4 (17.4%) pts showed radiological activity with no clinical correlates at 3 months (n=2), 4 months (n=1) and 9 months (n=1). EDSS was stable except for 1 aSP patient who showed 1-year disability progression. Safety: I) Infusion Associated Reactions (IARs) occurrence was significantly lower with respect to alemtuzumab courses (p<0.05); (ii) infections: mild upper airways (n=1), urinary infections (n=1), appendicectomy (n=1) and fever due to probable Sars-Cov2 infection (n=1). For 12 pts, data about immunophenotype were available. Of them, no pts showed T CD4+ cell count decrease <200 cell/mm3 at 3, 6-months and 1-year FU; complete B CD19+ cell depletion (<5 cell/mm3) was confirmed at 3, 6-months and 1-year FU. 10 (43.4%) pts developed hypogammaglobulinemia without developing associated infectious events. C) Autoimmunity: no alemtuzumab-related new complications occurred.

Conclusions

short-term FU seems to suggest that the switch to OCR in MS patients who showed disease activity after 2 ALM courses is characterized by a good safety and efficacy profile, although clinical and neuroradiological activity can be detected both in an early and in a later phase of treatment. Longer follow-up is warranted and recruitment is still ongoing.

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Clinical Outcome Measures Poster Presentation

P0179 - Using NIH Toolbox Standing Balance Test to quantify subtle balance impairment in patients with multiple sclerosis (ID 1648)

Speakers
Presentation Number
P0179
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Balance impairment is frequent in Multiple Sclerosis (MS). Attempts to measure balance deficits in clinical practice have mostly relied on EDSS, but its scarce capability to detect subtle deficits is an important limitation.

Objectives

To compare NIH Toolbox Standing Balance Test (SBT) with EDSS in detecting balance impairment in MS and to assess the contribution of the different Functional Systems (FS) involved in balance on SBT metrics.

Methods

128 consecutive MS patients and 36 age and sex-matched healthy controls (HCs) underwent NIH Toolbox SBT at the MS Center of the University of Genoa. Patients underwent clinical evaluation with EDSS FS recording and 3T brain MRI (Siemens Prisma). Theta scores (θ) were derived and corrected for age, sex, height and weight. T2 and T1 lesion volumes (LV) were obtained for the cerebellum and the total brain separately. A linear logistic regression model was performed to evaluate the relative contribution of cerebellar, sensory and brainstem impairment
on balance performance.

Results

92 (73.9%) MS patients were females, mean (SD) age was 41.2 (11.6) years; 108 (84.4%) patients had relapsing-remitting (RRMS) and 20 (15.6%) progressive MS (PMS). Mean disease duration was 10.6 (9.3) years, median (IQR) baseline EDSS was 2.5 (1-4). According to their FS, 73 (53.0%), 57 (44.5%) and 79 (61.7%) patients had no evidence of cerebellar, sensory and brainstem dysfunction respectively. On brain MRI, 95 (74.2%) patients exhibited cerebellar lesions [mean T2LV 0.31 (0.44) mL; mean T1LV 0.20 (0.31) mL]. Patients had significantly lower θ compared with HCs (-0.27vs0.91;p=0.003). RRMS had better performance than PMS patients (-0.05 vs -1.45;p=0.006). Patients with a cerebellar and brainstem FS=0 had higher θ than impaired patients (0.34vs-1.07;p&lt;0.0001 and 0.12vs-0.89;p=0.008 respectively). Patients without impairment in sensory and brainstem FS had worse performance than HCs (0.08vs0.91;p=0.046 and 0.12vs0.91;p=0.048, respectively). Each 1 point increase in cerebellar FS independently determined a -0.50 decrease in θ (95%CI:-0.91-0.09; p=0.017).  correlated with cerebellar T2LV and T1LV (Spearman r-0.29,p=0.001 and r=-0.28,p=0.001 respectively) but not with global T2LV and T1LV.

Conclusions

NIH Toolbox SBT is able to detect subtle balance impairment in MS patients, not detected by clinical examination. Clinical and radiological cerebellar involvement seem to be specifically related to NIH Toolbox SBT metric.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0344 - Injectable versus oral first-line disease-modifying therapies: results from Italian MS register (ID 1384)

Abstract

Background

The advent of oral first-line disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) has expanded considerably the therapeutic landscape. However, here is an important need to gather real-world evidence data regarding long-term treatment effectiveness and safety in comparison to the old first-line injectables DMTs.

Objectives

To compare old injectable and oral first line DMTs for time to first relapse, time to confirmed disability progression (CDP), and time to discontinuation in a cohort of RRMS patients extracted from the Italian MS Registry.

Methods

Multicentre, observational, retrospectively acquired and propensity-adjusted cohort study of RRMS-naïve patients in the Italian MS Register starting injective or oral first line DMTs between 1 January 2010 and 31 December 2017 to evaluate their impact on disability outcomes in patients. Enrolled patients were divided into two groups: injectable group (IG) and oral group (OG).

Results

From a cohort of 11,416 patients, 4,602 were enrolled (3,919 on IG and 683 on OG). IG had higher rate of women (67.3% vs 63.4%, p<.05) and a lower mean age (36.1±10.9 vs 38.9±11.8, p<.001). For the event time to first relapse, Cox models after PS adjustment revealed a lower risk for OG patients (HR 0.58 CI95% 0.47-0.70, p<0.001). About the risk of CDP, no differences were found in the two groups (HR 1.14 CI95% 0.88-1.48, p=0.306). About the risk of DMT discontinuation, OG patients showed lower risk (HR 0.70 CI95% 0.57-0.86 p=0.001) than IG patients.

Conclusions

Real-world data from the Italian MS registry suggest that first line oral DMTs are associated to lower risks of experiencing a new relapse and of therapy discontinuation in comparison to injectable DMTs.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0365 - Ocrelizumab treatment in patients with progressive multiple sclerosis: a single-center real-world experience (ID 1628)

Speakers
Presentation Number
P0365
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab (OCR) treatment in pivotal trials of patients (pts) with progressive multiple sclerosis (PMS) has demonstrated to slow disability worsening, with a good safety profile. However, real-word data on efficacy and adverse events (AE) are still scarce.

Objectives

To provide first experience data regarding efficacy and safety of OCR use in PMS pts treated within a real-world setting.

Methods

We collected safety and efficacy data from all PMS pts treated with OCR at the MS Center of the University of Genoa. The probability of disability-, relapse- and MRI activity-free survival and NEDA-3 status was calculated with Kaplan-Meier estimator and Cox proportional hazards regression analysis. AE were recorded throughout the follow-up (FU).

Results

We recorded data from 59 PMS pts [42 (71%) with primary-progressive (PP) MS and 17 (29%) with secondary progressive (SP) MS, 24 females (41), mean (SD) age 49.8 (8.2) years] with a mean disease duration (DD) of 12.1 (10.1) years, a median (IQR) baseline EDSS of 5.5 (3.5-6.0) and median number of previous DMTs 1 (0-2). SPMS patients had longer DD (20.8vs8.6; p=0.004) and had mean ARR of 0.24 (0.4). 21 (36%) pts had not received any DMT prior to OCR. Mean FU was 2.0 (1.1) years. 14 (24%) patients had an active MRI brain scan at baseline. At 1-year FU, MRI-inflammatory-activity-free survival was 87.3% (CI95%: 76.9-97.7%), relapse-free survival was 100% and progression-free survival was 82.7% (72.3-93.1%). NEDA-3 status was achieved in 72.3% (59.0-85.5%) of pts. No differences were noted between patients with PP and SPMS. At multivariate analyses, no baseline characteristic was found be predictive of a higher probability of progression-free survival, MRI-activity-free survival and NEDA-3 status. We recorded 69 AE in 36 pts (32 upper respiratory tract infections; 6 herpes simplex-1 reactivation; 7 lower urinary tract infections; 1 acute myeloid leukemia following myelodysplastic syndrome; 1 appendicitis treated with surgical procedure). No serious infusion-associated reactions were reported.

Conclusions

We report short-medium term efficacy data in a real-world population of progressive patients treated with OCR, including a relatively high proportion of patients without MRI activity at baseline assessment. Our data suggest that OCR should be considered as treatment option in both patients with PPMS and SPMS.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0410 - Treatment with ocrelizumab during Sars-Cov2 pandemic: efficacy and safety outcomes (ID 1787)

Speakers
Presentation Number
P0410
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Sars-Cov2 pandemic led neurologists to modify the therapeutic approach in Multiple Sclerosis (MS) care setting, especially with regard to immunodepleting treatments.

Objectives

to describe management and outcome of MS patients (pts) treated with ocrelizumab (OCR) during Sars-Cov2 pandemic in the MS Center of University of Genoa.

Methods

we collected data about pts scheduled to undergo OCR infusion from 1st March to 30th June 2020. Pts that previously underwent the first OCR infusion completed the induction cycle. No further OCR cycles during March and April 2020 were performed. Starting from May, we adopted an infusion scheme based on B-cell repopulation, differently applied for Relapsing Remitting (RR) and Progressive (P) pts. RRMS pts performed immunophenotype (IF) and received OCR infusion when B CD19+ cell count overcame the cut-off of 1%. Conversely, for PMS pts OCR infusions were delayed for 3 months. Then, PMS pts underwent OCR infusion based on B CD19+ cell monitoring. For pts with evidence of B CD19+ cells repopulation brain 3T MRI was planned before OCR re-infusion.

Results

77 MS pts were included [45 (58%) RRMS, 32 (41%) PMS; mean age 44.7 (SD: 11.1) years, mean disease duration 21.7 (22.3) years, mean number of previous DMT before OCR: 1.6 (1.6), mean number of previous OCR infusions 3.9 (SD 2.3). 11 (13.1%, 9 RR, 2 PP) of the 49 pts that performed a first IF presented B CD19+ cell repopulation and received OCR re-infusion, with a mean delay from scheduled infusion of 70 (48.9) days. The mean number of previous OCR infusions was 3.0 (1.2) and 3.1 (1.6) for pts with and without evidence of B-cell repopulation respectively. No effect of previous OCR infusions number on the probability to develop B CD19+ cell repopulation at the first IF was detected by ANCOVA analysis, correcting for the delay between the date of scheduled infusion and the date in which the first IF has been performed. Considering the global cohort, 1 pt presented a dubious sensory relapse with no evidence of radiological activity. None of the pts who performed brain MRI before OCR re-infusion showed new T2 or Gd+ enhancing lesions. 3 pts were infected by Sars-Cov2; 2 of them needed hospitalization but recovered completely.

Conclusions

the management of patients treated with OCR during Sars-Cov2 pandemic with a personalized infusion protocol based on B CD19+ cells repopulation was associated with good results in terms of efficacy and safety outcome

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Disease Modifying Therapies – Risk Management Poster Presentation

P0418 - Withdrawal of fingolimod treatment: results from a single-cohort observational study (ID 1604)

Speakers
Presentation Number
P0418
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Management of multiple sclerosis (MS) patients who discontinue fingolimod (FTY) is not established yet and breakthrough disease activity has been reported following fingolimod withdrawal. However, data regarding this phenomenon and its possible impact in the long-term are still sparse.

Objectives

To explore frequency of disease reactivation after FTY cessation in a single-center cohort and clinical/radiological characteristics of patients (pts) discontinuing FTY during (I) the wash-out period and (II) the first 12-months following a new treatment onset.

Methods

Data regarding relapses, Expanded Disability Status Scale (EDSS), MRI activity (new T2 and/or Gd-enhancing lesion) and lymphocyte count before and during FTY treatment, the wash-out period and the first 12-moths of a new treatment were retrospectively collected. Pts were grouped according to (I) discontinuation reason (inefficacy/adverse events/other reasons) and (II) disease activity during wash-out (no disease activity/at least one relapse or MRI activity/rebound). Differences in clinical/radiological characteristics or time to NEDA3-failure between groups were assessed with ANOVA, Chi-square and Kaplan-Meier estimator as appropriate.

Results

We included 71 pts [females:70%; mean age and disease duration at FTY start:37.6±8.4 and 11±7.6 years; median EDSS:3 (0-7); mean treatment duration:2.3 year]. 70% discontinued for inefficacy, 22% for adverse events, 8% for other reasons (pregnancy/pts’s choice). During the wash-out 69% of pts remained stable, 21.2% had clinical/radiological activity, 9.8% had a rebound (mean wash-out period: 2.3, 8.2, 4.1 months, respectively; p=0.03). Age was lower in rebound vs stable pts (28.5±4.9vs39.4±8.3; p=0.006). Discontinuation for inefficacy was observed in 70% of stable, 93% of clinically/radiologically active and 42% of pts with a rebound during wash-out (p<0.0001). No differences in time to NEDA3-failure during the first 12-months following a new treatment start were observed according to discontinuation reason or disease activity during wash-out (Log-Rank test: p=0.67 and p=0.23, respectively). Disease duration, EDSS, lymphocytes’ count at FTY stop and lymphocytes’ increase during wash-out did not differ according to disease activity during wash-out or response to following treatment.

Conclusions

Younger pts were more likely to have a rebound, while more frequent discontinuation for inefficacy and longer wash-out period were observed in pts with clinical/radiological activity during wash-out. Time to NEDA3-failure within the 12-months following a new treatment onset was not influenced by discontinuation reason or disease activity during wash-out

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Epidemiology Poster Presentation

P0506 - Towards a validated Secondary Progressive Multiple Sclerosis definition: A study from the Italian MS Register (ID 1432)

Abstract

Background

No clear metrics for sensitive and reliable identification of the transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive (SP)MS are available.

Objectives

To compare diagnostic performances of two different data-driven Secondary Progressive Multiple Sclerosis definitions.

Methods

patient with RRMS with a follow-up ≥5 years, with a current age ≥18 years, and with ≥3 EDSS scores recorded were selected from the Italian MS Registry. Annual incidence of SPMS conversion was reported as number of patients converting to SP every 100 patients/year. Three different SPMS definitions have been used. Data-driven definitions based on the Lorscheider’s algorithm (LA) and on the EXPAND trial inclusion criteria were validated, using the neurologist’s definition as gold standard, in terms of calibration, discrimination and goodness of fit by calculating: sensitivity, specificity, Positive Predictive Value (PPV), Negative Predictive Value (NPV), the Akaike information criterion (AIC), the Area Under the Curve (AUC). The overall calibration of the data-driven definitions was evaluated by the Calibration Slope test.

Results

a cohort of 10,240 RRMS patients was extracted from the Italian MS Registry. According to the neurologist judgment, 880 (8.59%) patients were classified as SPMS in the dataset. By applying the LA and the EXPAND definition, 1,806 (17.64%) and 1,134 (11.07%) patients, respectively, were classified as SPMS. The annual rate of SP conversion during the follow-up was 0.74 every 100 patients/year based on the neurologist’s definition, 1.57 every 100 patients/year using the LA and 0.94 every 100 patients/year applying the EXPAND definition. Both the data-driven definitions were well calibrated, with a p-value of the Calibration Slope test higher than 0.05 (LA=0.55; EXPAND definition=0.57). The AIC (LA=4301; EXPAND definition=5510) and the R-Square (LA=0.15 vs EXPAND definition=0.05), were in favor of the LA. The LA showed a greater discrimination power (AUC: 0.83 vs 0.65) and a higher sensitivity (77.1% vs 38.0%) in comparison to the EXPAND definition. Both definitions showed similar specificity (88.0% vs 91.5%). The PPV and the NPV were both higher using the LA than those obtained by the EXPAND definition (37.5% vs 29.5%; 97.6% vs 94.0%, respectively).

Conclusions

An accurate definition of SP transition is needed for a timely and efficacious treatment of SPMS patients. Real-world data from the Italian MS Registry suggests that data-driven definitions had a greater ability to capture SP transition than neurologist’s definition and that the global accuracy of LA seems to be higher than a definition based on the EXPAND trial inclusion criteria.

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Imaging Poster Presentation

P0652 - The relationship among leptomeningeal enhancement clinical, radiological activity and cerebrospinal fluid markers (ID 1593)

Speakers
Presentation Number
P0652
Presentation Topic
Imaging

Abstract

Background

Meningeal inflammation is a progressively recognized finding in multiple sclerosis (MS). The real prevalence of leptomeningeal enhancement (LME) in different stages of MS and its association with neurodegeneration is still a matter of debate.

Objectives

To assess the in-vivo prevalence of LME in relapsing-remitting MS (RRMS) and to evaluate the association with clinical/radiological activity and cerebrospinal fluid (CSF) markers.

Methods

This is an ongoing observational study. LME was assessed by two blinded neurologists on a 3D 1x1x1 mm3 Fluid-Attenuated-Inversion-Recovery (FLAIR) acquired 20 minutes post gadolinium (TR 6000 ms; TE 356 ms; Fat suppressed). LME was defined as signal intensity within the subarachnoid space greater than that of brain parenchyma and brighter on postcontrast scans. MRI activity was defined as at least 1 gadolinium enhancing and/or new/enlarging T2 lesions. Differences in terms of clinical, radiological, CSF metrics between patients with and without LME were tested with ANOVA, chi square and binary logistic regression analysis as appropriate.

Results

38 RRMS patients were included in the analysis: [65,2% female, mean age 37,8±10.1 years mean disease duration 10,1±9.2 years, median Expanded-Disability-Status-Scale (EDSS) 2 (0-6,5)]. 78,3% of patients had MRI activity in the previous 2 years: among them 17,4% had uniquely radiological activity and 60,9% had clinical relapses (experiencing disease progression in 17,4 % of cases), 26.1% had ongoing MRI activity. LME was found in 37% of patients, median number 1 (range 1-3). No difference in EDSS, age and disease duration was found between patients with or without nodules. LME prevalence was higher in patients with previous MRI activity (P=0.047). Multivariable models adjusted for baseline EDSS exploring predictive value of clinical progression, previous MRI activity, ongoing MRI activity show that previous MRI activity was the only variable associated with LME (p=0.002). CSF parameters had no predictive value for LME development nor any association was found between presence of oligoclonal bands and LME.

Conclusions

LME was found in a discrete proportion of RRMS patients and it was associated with previous, but not ongoing, radiological activity. A prospective clinical evaluation is needed in order to assess the prognostic value of our findings.

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Neuropsychology and Cognition Poster Presentation

P0793 - Clinical course impacts on the association between general cognition and mentalizing deficits in MS (ID 1614)

Speakers
Presentation Number
P0793
Presentation Topic
Neuropsychology and Cognition

Abstract

Background

Theory of Mind (ToM, i.e the ability to decode emotional states) is a cognitive function that plays a key role in social functioning. While ToM deficits have been found to be frequent in subjects with MS, ToM is not routinely assessed in formal neuropsychological assessments in this population. The lack of inclusion of ToM assessment in routine neuropsychological evaluation of MS patients, stems from different causes including a partial characterization of the association between general cognition and ToM in the different phases of the disease.

Objectives

To evaluate the interaction between clinical course (relapsing remitting MS (RRMS) vs progressive MS (PMS)), ToM deficits and general cognition. More in detail we aim to assess if the role played by general cognitive functioning on ToM is different in PMS rather than in RRMS

Methods

120 MS patients (age: 44.9±11.6 years, median EDSS 2.5 range 1-6; 75 subjects with RRMS and 45 with PMS) were assessed with the Symbol Digit Modalities Test (SDMT) to evaluate general cognition and the Reading the Mind in the Eyes Test (RMET) to evaluate ToM. The RMET, developed by Baron-Cohen and colleagues in 2001 is a standardized test that consists of 36 black and white picture of the eye region; the subject has to recognize the emotional state represented in the picture and choose one among four given words that depict an emotion.

Results

Comparing RRMS and PMS patients, there was a significant difference in SDMT (55.3±12.0 vs 40.2±11.0, p=0.001) and in total RMET (27.0±4.0 vs 22.9±3.0 p=0.001) scores. There was a significant correlation between SDMT and ToM in the whole sample (p<0.001, r=0.45) and in the RRMS group (p=0.001, r=0.48, but not in PMS (p=0.83) group.

Conclusions

The association between SDMT and RMET is modulated by clinical course in MS. This observation suggests that a bigger role is played by general cognition on RMET in RRMS rather than in PMS possibly due to the presence of more diffuse damage in PMS. Our data suggest that these two metrics change differently over the disease course and thus provide complementary information in the study of cognitive deficits in MS.

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Observational Studies Poster Presentation

P0913 - Risks associated with wash-out duration when switching from fingolimod to cell-depleting agents (ID 1317)

Abstract

Background

A wash-out duration lasting >1–2 months between the majority of sequential disease-modifying therapies (DMTs) is associated with an increased risk of disease reactivation in Multiple Sclerosis (MS) patients.

Fingolimod (FTY) induces sequestration of lymphocytes in secondary lymphoid organs and the average lymphocyte recovery following discontinuation takes 1-2 months. It has been hypothesized that the therapeutic effects of subsequent cell-depleting agents may be compromised if lymphocyte recovery is still incomplete and that shorter wash-out periods do not affect the disease reactivation risk.

Objectives

To assess the risk of relapses following FTY discontinuation and the initiation of a B/T cell-depleting agent initiation in relation to the duration of wash-out between the drugs using data from the Italian MS Registry.

Methods

Patients who initiated alemtuzumab, rituximab, ocrelizumab or cladribine within six months of FTY discontinuation, and with a follow-up of at least six months, or until a relapse occurred, were included in the study. The risk of relapses was assessed in relation to different wash-out durations (<6, 6-11, 12-17 and >/=18 weeks) using a Poisson regression analysis (and reported as incidence rate ratio - IRR) and a Cox proportional hazards model including age, disease duration, relapses during FTY treatment, EDSS and reason for FTY discontinuation as covariates.

Results

Inclusion criteria were met by 329 patients (226F, 103M; mean age 41±10 years). Following a median wash-out period of 11 weeks [IQR: 6-16], 175 patients started alemtuzumab, 69 rituximab, 68 ocrelizumab and 17 cladribine. Ninety patients relapsed during the wash-out period and 72 during the subsequent cell-depleting therapy. During the cell-depleting treatment, IRR for a relapse was significantly greater in patients with a washout-period of 12-17 (IRR (95%CI): 2.4 (1,1-5,5); p=0.037) and >/=18 weeks (6.0 (2.8-12.7); p<0.001) compared to the reference period (<6 weeks).

The multivariable Cox analysis showed that the time to a relapse was significantly influenced by the occurrence of relapses during FTY treatment (HR (95%CI): 1.4 (1.2-1.7); p<0.001). Moreover, wash-out durations of 6-11, 12-17 and >/=18 weeks were associated with a higher risk of a relapse in comparison to wash-out durations shorter than 6 weeks (3.8 (1.1-13.2); p=0.037; 6.0 (1.7-21.9); p=0.006; 16.3 (4.8-56.3); p<0.001, respectively).

Conclusions

The risk of relapses during a cell-depleting therapy following a sequestering agent, namely FTY, increases progressively with the duration of wash-out, underlining the need of a short wash-out period also in this type of treatment sequence.

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Reproductive Aspects and Pregnancy Poster Presentation

P1134 - Recovery of menstrual cycle in women with multiple sclerosis treated with autologous haematopoietic stem cell transplantation. (ID 1633)

Speakers
Presentation Number
P1134
Presentation Topic
Reproductive Aspects and Pregnancy

Abstract

Background

Autologous haematopoietic stem cell transplantation (aHSCT) is increasingly taken into consideration as a treatment strategy for patients with aggressive multiple sclerosis (MS). The chemotherapies used in the conditioning regimens for aHSCT are known to be responsible of amenorrhea in fertile women. Therefore, concerns on successful family planning in women with aggressive MS treated with aHSCT might rise.

Objectives

To assess fertility outcomes in women treated with aHSCT for aggressive MS considering different conditioning regimens.

Methods

We collected disease- and treatment-related characteristics from consecutive women with MS treated with aHSCT at the Italian MS centers of Genoa, Barletta and Cagliari. ANCOVA analyses and binary logistic regression were performed to assess the effects of baseline characteristics on fertility outcomes.

Results

We included 38 women [25(67%) with relapsing-remitting MS] with a mean age at aHSCT of 31.7(±6.7) years and a mean disease duration of 10.9(±6.0) years. Mean age of menarche was 12.3(±1.9) years. 31(82%) patients underwent transplant with a myeloablative cconditioning regimen while 7(18%) patients were transplanted with a low-intensity lymphoablative regimen. 26(68.4%) patients recovered menstrual cycle after a mean time of 5.7(5.2) months. Among these, 10(38%) patients had irregular periods (<21days;>35days apart) and 11(42%) had changes in the menstrual flow. Patients who recovered menstrual cycle were younger at the time of transplant (28.8vs37.7 years;p<0.0001) and had lower EDSS scores 1 year before aHSCT (4.7vs5.8;p=0.024). No significant differences were noted in terms of clinical phenotypes, age of menarche, body mass index, number of previous therapies, previous exposure to cyclophosphamide, mitoxantrone and the conditioning regimen used within aHSCT. A younger age was independently associated with a higher probability of recovery of menstrual cycle (OR=0.78;p=0.006). 3/27 patients (11%) with ≤35 years had persistent amenorrhea after aHSCT. We recorded 4 pregnancy after aHSCT (3 uncomplicated pregnancies and 1 spontaneous abortion). One patient repeatedly tried to conceive, both naturally and artificially, without success.

Conclusions

Younger age is independently associated with the recovery of menstrual cycle in women with MS treated with aHSCT, which is obtained in 89% of women under 35 years old. The use of a myeloablative conditioning regimen doesn’t seem to be associated with worse fertility outcomes.

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