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

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.

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.

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 1^st March to 30^th 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

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

Background

Cerebellar pathology is associated with worse cognitive performances in patients with multiple sclerosis (MS), but the structural correlates (in terms of single cerebellar lobules) of different cognitive domains (processing speed, episodic memory and visuospatial memory) are still unknown.

Objectives

To investigate the association of specific cerebellar lobules with impairment in different cognitive domains in MS.

Methods

Patients underwent 3T brain MRI (Siemens,Prisma) and neuropsychological evaluation with assessment of the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test (CVLT) and the Brief Visuospatial Memory Test (BVMT). 1x1x1mm T1-weighted images were used for cerebral and cerebellar segmentation. MS lesions were manually segmented on T1 and T2 weighted images.

Results

We included 70 pts [58(82.9%) with relapsing-remitting MS]; 52 females (74.3%), mean age 42.9(±11.1) years] with a mean disease duration of 12.4(± 10.1) years and a median (IQR) baseline EDSS of 2.5(1-4). Mean SDMT score was 54.3(±13.7), mean CVLT score was 57.9(±11.5) and mean BVMT score was 28.4(±6.5). Mean brain T2 lesion volume (LV) was 12,2(±12.3) mL, mean brain T1LV was 7.9(±9.0) mL, mean cerebellar T1LV and cerebellar T2LV were 0.2(±0.3) and 0.3(±0.5), respectively. 53(75.7%) pts had at least one cerebellar MS lesion. Mean normalized brain volume (NBV) was 1389(±131) mL and mean normalized grey matter volume (NGMV) was 602(±70) mL. Correlations were found between volumes of the posterior lobe of the cerebellum, lobule VIIIa, VIIIb, IX and X and CVLT scores (0.24<r<0.29, 0.015<p<0.046), with additional correlations of lobule X with BVMT values (r=0.29, p=0.016). Correlations were found between CVLT and BVMT scores and cerebellar T2 and T1LV (-0.29<r<-0.27, 0.017<p<0.024), but not with brain T2 and T1LV. NGMV was associated with SDMT score (r=0.26, p=0.032), but not with CVLT and BVMT scores. At multivariate analyses, accounting for the effects of age, sex, NGMV and cerebellar T2LV, atrophy of the posterior portion of the cerebellum was independently associated with worse performance at CVLT (p=0.038,B=0.19).

Conclusions

Atrophy of the cerebellar lobules VIIIa, VIIIb, IX and X is independently associated with episodic memory difficulties in MS patients, while processing speed seems to relate mostly to brain pathology.