Background

Worldwide multiple sclerosis (MS) centers have coordinated their efforts to use data acquired in clinical practice for real-world observational studies.

Objectives

In this retrospective study, we aim to harmonize outcome measures, and to evaluate their heterogeneity within the Rising Italian Researchers in MS (RIReMS) study group.

Methods

RIReMS members filled in a structured questionnaire evaluating the use of different outcome measures in clinical practice. Thereafter, thirty-four already-published papers from RIReMS centers were used for heterogeneity analyses, using the DerSimonian and Laird random-effects method to compute the between-study variance (τ²).

Results

Based on questionnaire results, we defined basic modules for diagnosis and follow-up, consisting of outcome measures recorded by all participating centers at the time of diagnosis, and, then, at least annually; we also defined more detailed/optional modules, with outcome measures recorded less frequently and/or in the presence of specific clinical indications. Looking at heterogeneity, we found 5-year variance in age at onset (ES=27.34; 95%CI=26.18, 28.49; p<0.01; τ²=4.76), and 7% in female percent (ES=66.42; 95%CI=63.08, 69.76; p<0.01; τ²=7.15). EDSS variance was 0.2 in studies including patients with average age <36.1 years (ES=1.96; 95%CI=1.69, 2.24; p<0.01; τ²=0.19), or from 36.8 to 41.1 years (ES=2.70; 95%CI=2.39, 3.01; p<0.01; τ²=0.18), but increased to 3 in studies including patients aged >41.4 years (ES=4.37; 95%CI=3.40, 5.35; p<0.01; τ²=2.96). The lowest variance of relapse rate was found in studies with follow-up duration ≤2 years (ES=9.07; 95%CI=5.21, 12.93; p=0.02; τ²=5.53), whilst the lowest variance in EDSS progression was found in studies with follow-up duration >2 years (ES=5.41; 95%CI=3.22, 7.60; p=0.02; τ²=1.00).

Conclusions

We suggest common sets of biomarkers to be acquired in clinical practice, that can be used for research purposes. Also, we provide researchers with specific indications for improving inclusion criteria and data analysis, ultimately allowing data harmonization and high-quality collaborative studies.

Background

The kappa index, calculated by dividing the cerebrospinal (CSF)/serum kappa free light chain (KFLC) ratio by the CSF/serum albumin ratio, is gaining increasing interest as an indirect marker of intrathecal activation of the humoral immune response. The demonstration of intrathecal synthesis is of particular relevance in the diagnostic work-up of suspected Multiple Sclerosis. However, the lack of consistent data on inter-laboratory agreement in CSF and serum KFLC measurements is one of the factors that hamper the use of kappa index in routine practice.

Objectives

Aim of this study was to assess agreement in CSF and serum KFLC measurements and kappa index values across different laboratories.

Methods

Fifteen paired CSF and serum samples were analyzed in all participating laboratories (nr=8). Four centers used Binding Site instruments and assays, 3 centers used Siemens instruments and assays, and one center used a Siemens instrument and a Binding Site assay.

Absolute individual agreement between laboratories was calculated using a two-way mixed effects intraclass correlation coefficient (ICC). Cohen's kappa coefficient was used to measure inter-laboratory agreement on positive (≥5.8) kappa index values.

Results

Within Binding Site laboratories, ICC for KFLC measurements was 0.96 (95%CI: 0.9-0.98) for CSF, 0.93 (95%CI: 0.63-0.98) for serum and 0.97 (95%CI: 0.94-0.99) for kappa index values. Within Siemens laboratories, ICC for KFLC measurements was 0.99 (95%CI: 0.97-100) for CSF, 0.93 (95%CI: 0.48-0.98) for serum and 0.95 (95%CI: 0.89-0.98) for kappa index values. ICC calculated for all laboratories was 0.93 (95%CI: 0.87-0.97) for CSF KFLC, 0.81 (95%CI: 0.53-0.93) for serum KFLC and 0.65 (95%CI: 0.43-0.84) for kappa index. Cohen's kappa coefficient for a positive kappa index was 0.89 across Binding Site laboratories, 0.70 across Siemens laboratories, and 0.77 across all laboratories.

Conclusions

There was an excellent agreement in CSF KFLC measurements and in kappa index values within laboratories using the same instrument and assay (Binding Site or Siemens), while serum KFLC measurements were less concordant. Agreement across all laboratories was decreased when including the laboratory using a Siemens instrument coupled with a Binding Site assay in the analyses. Concordance for a positive kappa index was substantial across all laboratories and within Siemens laboratories, and very good within Binding Site laboratories.

Background

Ocrelizumab (OCR) is a new a humanized monoclonal antibody able to bind to a specific epitope of CD20, expressed in the majority of B-cell lines. OCR has been approved for treatment of aggressive relapsing-remitting Multiple Sclerosis (RR-MS) and for primary progressive MS.

Objectives

To evaluate the clinical and radiological outcomes in a cohort of RR-MS patients after switching from other second line treatments (Natalizumab – NTZ, Fingolimod - FTY or Alemtuzumab - ALEM) to OCR. We also evaluated safety of OCR treatment

Methods

All consecutive patients (pts), evaluated in the City of Health and Science University Hospital of Turin MS Center, switching to OCR from other second line treatment, were included in the study. Study outcomes were: clinical disease activity (EDSS progression, relapses), radiological disease activity (new/enlarging T2 lesions, T1 Gd+ lesions) evaluated by MRI scans at 3, 6 and 12 months after starting OCR compared with a reference MRI scan performed within one month before switching, and treatment safety (any infusion reaction and/or adverse event related to OCR therapy).

Results

We identified 42 patients (mean age 42±9 years, 27 (64%) female, mean Expanded Disability Status Scale 4) who switched from NTZ (23 pts), FTY (16 pts) and ALEM (3 pts) to OCR between January 2019 to June 2020. Mean disease duration from MS diagnosis to start of OCR was 11±6 years. Reasons for switch were: persistence of disease activity (23 patients), PML risk (17 pts) or tolerability (2 pts). Mean washout period was 60 days after NTZ and 45 days after FTY. During the follow-up period (mean 10±2 months) no significant adverse events were observed during OCR treatment: 6 pts (14%) had minor infusion reactions, no serious infections were reported. Switching to OCR appears to be effective in most patients: 4/42 (1pt switched from FTY, 3 pts from NTZ) had a relapse treated with corticosteroids, occurring within 4 months after starting OCR. One patient experienced an early rebound of disease activity within 6 weeks after stopping FTY, before switching to OCR. MRI follow-up showed new/enlarging T2 lesions in 4 patients (3 switching from FTY and 1 from NTZ), on average 7 months after starting OCR, and a T1 Gd+ lesion in one patient switching from FTY (3 months after starting OCR). All other patients did not show clinical or radiological disease activity.

Conclusions

In our single Center cohort, switching to OCR from other second line treatments appears to be safe and in most patient effective.

Background

Cervical spinal cord atrophy is an MRI biomarker of neurodegeneration and in MS it correlates with disability and disease progression. The Mean Upper Cervical Cord Area (MUCCA) can be used to measure this atrophy. Recently there has been an increasing interest towards calculating the MUCCA from MR brain images. It has been shown that MUCCA measurements calculated from brain T1-weighted images are comparable with those calculated from cervical cord T1-weighted images. Moreover, gadolinium (Gd) administration seems to have no effect on these measurements.

Objectives

To evaluate the correlation and the agreement between MUCCA measurements calculated from 3D-FLAIR and 3D-T1 post Gd brain images.

Methods

We used the images of 20 patients with Progressive MS who underwent a 1.5 T MRI as a routine radiological follow-up. 3D- FLAIR and post Gd 3D-T1 brain images were acquired. In our study, MUCCA was defined as the mean cross-sectional area (CSA) of a 12.8 mm long section of the cervical spinal cord, starting from the tip of the C1 vertebra. 3D-FLAIR and 3D-T1 were co-registered and resampled to the same voxel size. The MUCCA and the CSA per slice were compared.

Results

The mean difference between the MUCCA measurements from FLAIR and T1 images was 1.12 mm² (1.9 %), range -3.13 mm² (5.4 %) - 4.18 mm² (7.2%). High positive correlation was observed between the MUCCA measurements from FLAIR and T1 images (r= .976 , p < .0001) and between the CSA per slice measurements from FLAIR and T1 images (r = .940 , p < .0001). High agreement was shown also by inspection of the Bland Altman plot.

Conclusions

Excellent correlation was observed between the MUCCA from 3D-FLAIR and post Gd 3D-T1 brain images. Hence 3D-FLAIR brain images, which are largely used in routine radiological follow-up, may be used to measure the MUCCA, allowing retrospective studies on spinal cord atrophy in addition to prospective ones. Further studies are needed to validate this approach, especially comparing 3D-FLAIR brain images with 3D-T1 spinal cord images.

Background

Extending the natalizumab interval after the 24th administration could reduce the risk of progressive multifocal leukoencephalopathy (PML) without efficacy reduction.

Objectives

To evaluate the non-inferiority of the efficacy of an extended interval dosing (EID) regimen compared with the standard interval dosing (SID) of natalizumab regarding the multiple sclerosis (MS) MRI activity.

Methods

It is an observational, multicenter (14 Italian centers), retrospective cohort study, starting from the 24th natalizumab infusion to the loss of follow-up or 2 years after baseline. Patients were grouped in 2 categories according to the mean number of weeks between doses: < 5 weeks, SID; ≥ 5 weeks, EID. Three hundred and eight patients were enrolled. Median dose interval (MDI) following 24th infusion was 5 weeks, with a bimodal distribution (modes at 4 and 6 weeks).

Results

Two hundred and sixteen patients were in the SID group (MDI = 4.4 weeks) and 144 in the EID group (MDI 6 weeks). The risk to develop active lesions on MRI is similar in SID and EID groups during the 6 and 12 months after the 24th natalizumab infusion, respectively 2.98% (95% CI: 0.56-5.40) vs 3.32% (95% CI: 0.00-6.65%) [p=0.88] and 6.65% (95% CI: 3.02-10.29) vs 5.67% (95% CI: 1.76-9.58%) [p=0.73]. The EID regimen does not increase the occurrence of MRI activity after 6 and 12 months.

Conclusions

There is no evidence of a reduced efficacy of natalizumab in an EID setting regarding the MRI activity. This observation confirms previous clinical results and together with the increasing evidence of a reduced risk of PML associated to an EID regimen, supports the need of a bigger randomized study to assess the need to change the standard of the natalizumab dosing schedule, in order to better manage JCV-positive patients after 24 doses of natalizumab.

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.