G. Izquierdo
Hospital Universitario Virgen Macarena

Author Of 7 Presentations

 On-Demand Program
Biostatistical Methods Poster Presentation

P0018 - Variability of the response to immunotherapy among sub-groups of patients with multiple sclerosis (ID 1239)

Speakers
Authors
Presentation Number
P0018
Presentation Topic
Biostatistical Methods

Abstract

Background

Our current understanding of demographic and clinical modifiers of the effectiveness of multiple sclerosis (MS) therapies is limited.

Objectives

To assess whether patients’ response to disease modifying therapies (DMT) in MS varies by disease activity (annualised relapse rate, presence of new MRI lesions), disability, age, MS duration or disease phenotype.

Methods

Using the international MSBase registry, we selected patients with MS followed for ≥1 year, with ≥3 visits, ≥1 visit per year. Marginal structural models (MSMs) were used to compare the hazard ratios (HR) of 6-month confirmed worsening and improvement of disability (EDSS), and the incidence of relapses between treated and untreated periods. MSMs were continuously re-adjusted for patient age, sex, pregnancy, date, time from first symptom, prior relapse history, disability and MRI activity.

Results

Among 23 687 patients with relapsing MS, those on DMT experienced 20% greater chance of disability improvement [HR 1.20 (95% CI 1.0-1.5)], 47% lower risk of disability worsening [HR 0.53 (0.39-0.71)] and 51% reduction in relapses [HR 0.49 (0.43-0.55)]. The effect of DMT on relapses and EDSS worsening was attenuated with longer MS duration and higher prior relapse rate. The effect of DMT on EDSS improvement and relapses was more evident in low EDSS categories. DMT was associated with 51% EDSS improvement in patients without new MRI lesions [HR 1.51 (1.00-2.28)] compared to 4% in those with MRI activity [HR 1.04 (0.88-1.24)]. Among 26329 participants with relapsing or progressive MS, DMT was associated with 25% reduction in EDSS worsening and 42% reduction in relapses in patients with relapsing MS [HR 0.75 (0.65-0.86) and HR 0.58 (CI 0.54-62), respectively], while evidence for such beneficial effects of treatment in patients with progressive MS was not found [HR 1.11 (0.91-1.46) and HR 1.16 (0.91-1.46), respectively].

Conclusions

DMTs are associated with reduction in relapse frequency, progression of disability, and increased chance of recovery from disability. In general, the effectiveness of DMTs was most pronounced in subgroups with shorter MS duration, lower EDSS, lower relapse rate and relapsing MS phenotype.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

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

Speakers
Authors
Presentation Number
P0248
Presentation Topic
Diagnostic Criteria and Differential Diagnosis

Abstract

Background

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

Objectives

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

Methods

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

Results

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

Conclusions

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

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

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

Speakers
Authors
Presentation Number
P0324
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

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

Objectives

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

Methods

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

Results

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

Conclusions

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

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Observational Studies Poster Presentation

P0862 - Disability accrual in primary-progressive & secondary-progressive multiple sclerosis (ID 1232)

Speakers
Authors
Presentation Number
P0862
Presentation Topic
Observational Studies

Abstract

Background

Some cohort studies have reported similar onset age and disability accrual in primary and secondary progressive MS (PPMS, SPMS); others have reported later onset and faster disability accrual in SPMS. Comparisons are complicated by differences in baseline disability and exposure to disease-modifying therapies (DMT), and by lack of a standardized definition of SPMS.

Objectives

We compared hazards of disability accrual in PPMS and SPMS patients from the MSBase cohort using multivariable Cox models, applying validated diagnostic criteria for SPMS (Lorscheider et al., Brain 2016).

Methods

Inclusion required adult-onset progressive MS; ≥ 3 recorded Expanded Disability Status Scale (EDSS) scores; and, for SPMS, initial records with EDSS ≤ 3 to allow objective identification of SPMS conversion. Phenotypes were subgrouped as active (PPMS-A, SPMS-A) if ≥ 1 progressive-phase relapse was recorded, and inactive (PPMS-N, SPMS-N) otherwise. Disability accrual was defined by sustained EDSS increases confirmed over ≥ 6 months. Hazard ratios (HR) for disability accrual were obtained using Andersen-Gill Cox models, adjusted for sex and time-varying age, disability, visit frequency, and proportion of time on DMT or immunosuppressive therapy. Sensitivity analyses were performed using (1) PPMS and SPMS diagnosed since 1995, and (2) physician-diagnosed SPMS. Cumulative probability of reaching EDSS ≥ 7 (wheelchair required) was assessed (Kaplan-Meier).

Results

5461 patients were included (1257 PPMS-N; 1308 PPMS-A; 1731 SPMS-N; 1165 SPMS-A). Age at progression onset was older in SPMS than PPMS (47.2 ± 10.2, vs. 41.5 ± 10.7 [mean ± SD]), and in the inactive subgroups of each phenotype. Hazard of disability accrual was decreased in SPMS relative to PPMS (HR 0.85; 95% CI 0.78–0.92); decreased by proportion of time on DMT (HR 0.99 per 10% increment; 0.98–0.99); and higher in males (1.18; 1.12–1.25). Relative to PPMS-N, hazard was decreased in SPMS-A (0.79; 0.71–0.87) but similar for PPMS-A (1.01; 0.93–1.10) and SPMS-N (0.94; 0.85–1.05). Sensitivity analyses corroborated these results. However, patients with SPMS-A reached EDSS ≥ 7 at younger ages (cumulative probability 30% by 57, vs. 64–66 for SPMS-N, PPMS-A, PPMS-N).

Conclusions

Progressive phase onset is later in SPMS than PPMS. Hazard of disability accrual during the progressive phase is lower in SPMS than PPMS. However, patients with SPMS-A reach wheelchair requirement younger than other progressive phenotypes, reflecting earlier progression onset versus SPMS-N, and greater disability at onset versus PPMS

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Observational Studies Poster Presentation

P0876 - High and low efficacy therapy in secondary progressive multiple sclerosis after accounting for therapeutic lag. (ID 760)

Speakers
Authors
Presentation Number
P0876
Presentation Topic
Observational Studies

Abstract

Background

In secondary progressive multiple sclerosis (SPMS), reduction in the rates of disability accrual after starting disease modifying therapy (DMT) has largely been limited to patients with ongoing inflammatory activity. A delayed treatment effect, termed therapeutic lag, may obscure therapeutic benefits in SPMS.

Objectives

To compare the effect of high and low efficacy DMT on disability outcomes in patients with recently active and inactive SPMS after accounting for therapeutic lag.

Methods

Using data from MSBase, a multinational MS registry, and OFSEP, the French MS registry, we identified patients with SPMS as per a previously validated objective definition. We identified patients treated with high- (natalizumab, alemtuzumab, mitoxantrone, ocrelizumab, rituximab, cladribine, fingolimod) or low-efficacy (interferons, glatiramer acetate, teriflunomide) DMT after SPMS onset. Based on our previous work, an individualised estimate of duration of therapeutic lag was calculated for each patient. Only events that occurred after the estimated therapeutic lag period were included in the analysis. Propensity score matching was used to select groups with comparable baseline characteristics. Disability and relapse outcomes were compared in paired, pairwise-censored analyses adjusted for visit density.

Results

Of 7359 patients with SPMS, 1000 patients fulfilled the criteria for study inclusion (510 active SPMS, 490 inactive SPMS). For the relapse outcomes, patients with active SPMS treated with high-efficacy DMTs experienced lower probabilities of relapses than low-efficacy DMTs (hazard ratio [HR] 0.7 [95%CI 0.5-0.9], p=0.006). Patients with inactive SPMS had similar probabilities of relapses in the high and low efficacy DMT groups (0.8 [0.6-1.2], p=0.39). No difference in the risk of 6-month sustained disability accumulation, or proportion of patients reaching EDSS>=7, was observed between groups when accounting for therapeutic lag.

Conclusions

The risk of disability accumulation in SPMS seems to be comparable in patients treated with high- and low- efficacy DMT. High efficacy DMT is superior to low efficacy therapy in reducing relapse activity in patients with active SPMS, but not those with inactive SPMS. Pre-treatment inflammatory activity, clinical or radiological, is a treatable target in SPMS which may benefit from higher-efficacy anti-inflammatory therapies.

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Observational Studies Poster Presentation

P0907 - Real-world experience with Cladribine Tablets in the MSBase Registry (ID 1587)

Speakers
Authors
Presentation Number
P0907
Presentation Topic
Observational Studies

Abstract

Background

Cladribine tablets are approved for treatment of multiple sclerosis (MS) in many jurisdictions. Real-world outcomes data is very limited.

Objectives

We analysed the cladribine treatment experience in the MSBase registry. We described baseline characteristics, treatment pathways, and relapse and discontinuation outcomes in patients with ≥6 months follow-up data from cladribine initiation.

Methods

We performed a secondary data analysis using MSBase Registry data of patients with a confirmed diagnosis of MS and newly treated with cladribine tablets after regulatory approval. Descriptive statistics were used to analyze baseline patient characteristics recorded within 3 months prior to cladribine tablets initiation, including demographics, disease course and duration, prior disease modifying drugs (DMD), and Expanded Disability Status Scale (EDSS).

Results

As of the 4th June 2020, MSBase included 660 patients treated with cladribine from 9 countries, mainly from Australia and Europe. A total of 576 met all inclusion criteria. These included 496 relapsing-remitting MS (RRMS) patients. In these, median age at cladribine tablets start was 45 years and median disease duration since clinically isolated syndrome was 12.6 years. Median EDSS at cladribine tablets start was 2.5. Around 13% of all RRMS patients initiated cladribine tablets as first line therapy. Of all RRMS patients switching to cladribine tablets with a treatment gap of <6 months, the most common immediate prior DMDs were fingolimod (17%), followed by natalizumab, teriflunomide and dimethylfumarate (all appx. 10%). Total follow-up time was 340 patient-years. Annualised relapse rate (ARR) on cladribine tablets was 0.12 (95%CI 0.09-0.17), compared to a pre-cladribine ARR of 0.38. Treatment persistence was 95% after 12 months (95%CI 91-98%), and 92% after 24 months (95%CI 87-96%).

Conclusions

This study characterizes RRMS patients treated with cladribine tablets in a real-world clinic setting. First-line use was uncommon. ARR was low, consistent with clinical trial data, and early discontinuations were very rare.

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Observational Studies Poster Presentation

P0909 - Real-world experience with Ocrelizumab in the MSBase Registry (ID 1559)

Speakers
Authors
Presentation Number
P0909
Presentation Topic
Observational Studies

Abstract

Background

Ocrelizumab (OCR) is a humanised anti-CD20+ monoclonal antibody approved for the treatment of primary progressive multiple sclerosis (PPMS), and relapsing forms of MS, including both relapsing-remitting (RRMS) and secondary progressive MS (SPMS) with relapses.

Objectives

In a real-world setting, to describe 1) baseline characteristics of patients with MS treated with OCR, 2) treatment pathway across lines of therapy up to initiation of OCR, and 3) initial clinical experience in patients with ≥6 months follow-up data from OCR initiation.

Methods

Secondary data analysis using MSBase Registry data including patients with a confirmed diagnosis of MS and started OCR therapy within 3 months prior to or at time of MSBase eligible/initial visit. Descriptive statistics were used to analyze baseline patient characteristics' recorded within 3 months of OCR initiation, including demographics, disease course and duration, prior disease modifying therapies (DMT), and EDSS. Occurrence of relapse was analyzed in patients with ≥6 months follow-up data from OCR initiation.

Results

As of 4th June 2020, MSBase included 2531 patients newly treated with OCR, of whom 1679 had an EDSS evaluation within 3 months of OCR start. There were 1185 patients with RRMS, 236 with SPMS, and 183 with PPMS. Median age at OCR initiation was 41.9 years, 49.5 years, to 50.1 years in RRMS, SPMS, and PPMS, respectively. Mean disease duration from symptom onset up to OCR initiation was longer in SPMS (19.7 years) than in RRMS (10.6 years) and PPMS (9.7 years). OCR was initiated as first line therapy in 17.5%, 5.5%, and 54.2% of RRMS, SPMS, and PPMS patients respectively. Most frequent previous DMT’s in RRMS were fingolimod (25.7%) and natalizumab (23.5%). 693 patients with RRMS had ≥6 months follow-up during OCR exposure. Of these, 643 remained relapse free (93%; 95% CI 86.0, 100.0) over a mean OCR exposure of 1.23 years. The annualized relapse rate (ARR) was 0.08 (95% CI 0.06-0.10), compared to an ARR of 0.85 in the 24 months pre-OCR start. In the overall cohort, treatment persistence at 12 and 24 months was 98.4% (95% CI: 97.3-9.1%) and 92.5% (95%CI 89-95%), respectively.

Conclusions

This study characterizes an international population of patients with RRMS, PPMS, and SPMS newly treated with OCR in a real-world clinical setting. First-line use was uncommon in RRMS and SPMS. During OCR treatment, ARR was below 0.1, and OCR discontinuations were very rare.

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