Background

There is limited evidence on the effects of disease modifying therapies (DMTs) on MS symptoms, health-related quality of life (HRQoL) and employment outcomes, particularly the comparative effectiveness between different available DMTs.

Objectives

By using the prospectively collected patient-reported data in the Australian MS Longitudinal Study (AMSLS) from 2015 to 2017, we aimed to compare natalizumab to other DMTs in relation to employment outcomes, MS symptom severity, HRQoL, and progression in the previous 12 months.

Methods

Medication and Disease Course surveys were conducted in 2015, 2016 and 2017, and collected data on DMTs, severity of 13 MS symptoms (0-10 scale), disability, HRQoL by European Quality of Life with five dimensions (EQ-5D) and work productivity loss (absenteeism, presenteeism, total work productivity loss in the previous 4 weeks). We used marginal structural models to estimate causal effect of natalizumab versus other DMT comparators (any other DMT, classic injectables, oral therapies (teriflunomide and dimethyl fumarate), higher efficacy DMTs (fingolimod, alemtuzumab and mitoxantrone), fingolimod, and alemtuzumab), while adjusting for time-varying confounders and intermediates of treatment effects.

Results

The analysis included 2836 observations. Compared to any other DMTs, natalizumab was associated with superior effects over time on improving balance, vision symptoms, sensory symptoms, bladder symptoms, sexual dysfunction, and feelings of anxiety. The strongest effect was seen for improving sensory problems (mean coefficient -0.44 (-0.66 to -0.22) per year). There was no evidence of an effect of natalizumab over time on improving HRQoL measured by the EQ-5D, but use of any other DMTs were associated with a significant decrease in EQ-5D. The use of natalizumab was associated with a marginal decrease in self-reported progression in the previous 12 months while the use of injectable DMTs and fingolimod were associated with an increased self-reported progression. The use of natalizumab was associated with a reduction in work productivity loss due to absenteeism compared to a worsening for any other DMT, and similar trends were less pronounced for presenteeism and total work productivity loss.

Conclusions

Compared to other DMTs, the use of natalizumab was associated with superior effects over time for several MS symptoms and absenteeism.

Background

Historically, disease activity diminished during pregnancy in women with relapsing-remitting MS. Today, women with high disease activity are more likely to attempt pregnancy due to the disease control that new therapies offer. But disease activity during pregnancy in the modern day remains understudied.

Objectives

Describe disease activity in a modern pregnancy cohort, grouped by preconception disease-modifying therapy (DMT) class; determine the predictors of relapse during pregnancy.

Methods

Data were obtained from the MSBase Registry. Term/preterm pregnancies conceived from 2011-2019 were included. DMT were classed by low, moderate and high-efficacy. Annualized relapse rates (ARR) were calculated for each pregnancy trimester and 12 months either side. Predictors of relapse during pregnancy were determined using clustered logistic regression.

Results

We included 1640 pregnancies from 1452 women. DMT used in the year before conception were none (n=346), low (n=845), moderate (n=207) and high-efficacy (n=242). Most common DMT in each class was interferon-beta (n=597), fingolimod (n=147) and natalizumab (n=219) for low, moderate and high-efficacy respectively. Conception EDSS ≥2 was more common in higher efficacy DMT groups (high: 41.3%; moderate 28.5%; low 22.4%; none 20.2%). For low-efficacy and no DMT groups, ARR fell through pregnancy. ARR of the moderate-efficacy group increased in the 1^st pregnancy trimester (0.55 [95% CI 0.36-0.80] vs 0.14 [95% CI 0.10-0.21] on low-efficacy), then decreased to a trough in the third. Conversely, ARR steadily increased throughout pregnancy for those on high-efficacy DMT (3^rd trimester: 0.42 [95% CI 0.25-0.66] vs 0.12 [95% CI 0.07-0.19] on low-efficacy). Higher efficacy DMT groups were associated with higher ARR in the early postpartum period (high: 0.84 [95% CI 0.62-1.1]; moderate: 0.90 [95% CI 0.65-1.2]; low: 0.47 [95% CI 0.38-0.58]). Preconception use of high and moderate-efficacy DMT and higher preconception ARR were predictors of relapse in pregnancy. But, continuation of high-efficacy DMT into pregnancy was protective against relapse (odds ratio 0.80 [95% CI 0.68-0.94]). Age ≥35 years was associated with reduced odds of relapse.

Conclusions

Women with RRMS treated with moderate or high-efficacy DMT are at greater risk of relapse during pregnancy. Careful pregnancy management, and use of long-acting high-efficacy DMT preconception, or continuing natalizumab into pregnancy, may prevent relapse in pregnancy.

Background

As the COVID-19 pandemic amplifies, efforts to minimise the risk on vulnerable people are essential. People with multiple sclerosis (MS) may be a vulnerable group due to the high proportion taking long-term immunosuppressive disease-modifying therapies (DMTs). Studies from Italy and France suggest older age, higher disability and progressive MS are associated with severe COVID-19, yet there remains uncertainty around the influence of DMTs.

Objectives

Given the many approved MS DMTs and the relatively low frequency of COVID-19 in MS patients per country, international data sharing is desirable to examine the impact of DMTs on COVID-19 severity. Here, we present the first results of the COVID-19 in MS global data sharing initiative of the MS International Federation and MS Data Alliance and many other data partners to inform MS clinical management during the COVID-19 pandemic.

Methods

Clinician-reported data from 21 countries were aggregated into a dataset of 1540 patients. Characteristics of admission to hospital, admission to intensive care unit (ICU), need for artificial ventilation, and death, were assessed in patients with confirmed or suspected COVID-19 infection using log-binomial regression. Adjusted prevalence ratios (aPR) were calculated adjusting for age, sex, MS type, and Expanded Disability Status Scale (EDSS).

Results

Of 1540 patients, 476 (30.9%) with suspected and 776 (50.4%) with confirmed COVID-19 were included in the analysis. Older age, progressive MS and higher EDSS were associated with higher frequencies of severe outcomes. Anti-CD20 DMTs, ocrelizumab and rituximab, were positively associated with hospital admission (aPRs=1.19 & 1.58), ICU admission (aPRs=3.53 & 4.12), and the need for artificial ventilation (aPRs=3.17 & 7.27) compared to dimethyl fumarate. Higher frequencies of all three outcomes were associated with combined anti-CD20 DMT use compared to all other DMTs (hospitalisation aPR=1.49; ICU aPR=2.55; ventilation aPR=3.05) and compared to natalizumab (hospitalisation aPR=1.99; ICU aPR=2.39; ventilation aPR=2.84). Importantly, associations persisted on restriction to confirmed COVID-19 cases and upon exclusion of each contributing data source in turn. No associations were observed between DMTs and death.

Conclusions

This study used the largest federated international cohort of people with MS and COVID19 currently available. We demonstrate a consistent association of anti-CD20 DMTs with hospitalisation, ICU admission and use of artificial ventilation suggesting their use among MS patients at risk for COVID-19 exposure may be a risk factor for more severe COVID-19 disease. To address study limitations, further research incorporating comorbidities, smoking and body mass index is required. Alternative study designs are needed to address questions on COVID-19 susceptibility among people with MS.

Background

The concept of no evidence of disease activity-3 (absence of brain MRI and clinical disease activity; NEDA-3) in multiple sclerosis (MS) reflects disease activity with limited sensitivity. The added value of neurofilament light chain levels in serum (sNfL) to NEDA-3 has not yet been investigated.

Objectives

To assess whether sNfL allows to identify among patients with and without NEDA-3 status those at higher risk of future disease activity and accelerated brain volume loss.

Methods

We analyzed 369 samples from 155 early relapsing-remitting MS patients (SET study). sNfL levels and brain MRI scans were evaluated annually. The comparison of subgroups defined by high or low sNfL (>90^th or <90^th percentile of healthy controls of the same age) and NEDA-3 status was performed by generalized estimating equation models. Changes in global and regional brain volumes were calculated on three-dimensional T1-weighted scans.

Results

Patients with disease activity (EDA-3) in the preceding year and high sNfL, compared to those with low sNfL, had: a) higher odds of EDA-3 in the following year (87% versus 58%; OR 4.39, 95%-CI:2.18, 8.94; p<0.001), b) greater whole brain volume loss during the following year (0.39%, 95%-CI:-0.63, -0.16; p<0.001) and c) greater whole brain volume loss (0.61%, 95%-CI:-0.66, -0.17; p<0.001) during the preceding year. Accordingly, NEDA-3 patients with high sNfL showed a trend for a return of disease activity (EDA-3) in the following year compared with those with low sNfL (57% versus 31%).

Conclusions

High sNfL levels are associated with increased future risk of disease activity and accelerated brain volume loss. Adding of sNfL improves the prognostic value of the NEDA-3 concept.

Background

Prevention of disability over the long-term is the main treatment goal in multiple sclerosis (MS), however, randomized clinical trials provide only short-term (3-6-month) treatment effect on disability.

Objectives

To externally validate the previously developed sustained progression score which established 6-month confirmed disability progression events as indicators of long-term disability worsening in randomized double-blind CLARITY (Cladribine Tablets Treating MS Orally) trials. A higher score indicates a greater probability of a progression event to be sustained over the long-term.

Methods

Data from the CLARITY and CLARITY 2-year Extension study were used. The 3-and 6-month confirmed disability progression events and the time over which progression remained sustained were identified. Patient characteristics at the time of progression previously associated with the likelihood of improvement after confirmed progression event (age, primary progressive MS, a relapse in previous month, expanded disability status scale score≥6 and its change from baseline, number of affected functional system domains, and worsening in pyramidal, brainstem and sensory domains) were used to calculate the sustained progression score for each progression event. A Cox proportional hazards model was used to validate the association of the score calculated for each 6-month confirmed disability progression event with time to improvement. To demonstrate application of the score in trial setting, the analysis of the CLARITY study were repeated estimating the effect of therapy on long-term disability outcomes. Effect of cladribine on 3-month confirmed progression events with any score and score˃1.5 was evaluated.

Results

A total of 667 6-month confirmed disability progression events were identified in the combined dataset, of which only 12 were followed by a 6-month confirmed disability improvement. The external validation of the score illustrated a trend towards a decrease in the likelihood of disability improvement in progression events with higher score (Hazard Ratio HR=0.72, 95% CI: 0.21-2.42). Results of the original trial were confirmed in addition to that oral cladribine reduced the risk of disability progression that was likely to be sustained over the long-term (only events with score˃1.5; HR: 0.64; 95% CI: 0.47-0.87).

Conclusions

The sustained progression score, estimated using the characteristics of confirmed progression events, provides important complementary information that will allow future trials to establish the effect of therapy not only on short-term but also on long-term disability accrual.

Background

Serum neurofilament light chain (sNfL) levels reflect only neuro-axonal injury that took place within 3-6 months prior to the date of sampling. Therefore, the frequency of assessment of sNfL levels for monitoring of disease activity warrants further investigation.

Objectives

To determine differences in accuracy of sNfL levels to detect radiological disease activity during the preceding 6 versus 12 months of follow-up.

Methods

This observational study included 148 patients with early relapsing-remitting multiple sclerosis (MS) from the SET cohort. Based on brain MRI performed at 0, 6 and 12 months, we assessed the ability of categorized sNfL measured at 12 months to reflect the presence of combined unique active lesions, defined as new/enlarging lesion compared with MRI performed in the previous 6 versus 12 months or contrast-enhancing lesion (e.g., active lesions).

Results

Together, 91% (95% CI=85-98%) of patients with ≥1 active lesion during the last 6 months and 84% (95% CI=77-92%) of patients with ≥1 active lesion during the last 12 months had sNfL≥30^th percentile. Among the patients with sNfL<30^th percentile, 14 (33.3%) developed ≥1 active lesion during the last 12 months, but only 6 (14.3%) developed ≥1 active lesion during the last 6 months. Among patients with sNfL<30^th percentile, 6 (14.3%) developed ≥2 active lesions during the last 12 months, but only 2 (4.8%) developed ≥2 active lesions during the last 6 months.

Conclusions

Low levels of sNfL better identified MS patients with the absence of recent radiological disease activity during the previous 6 than the previous 12 months. In the future, assessment of sNfL at least every 6 months may substitute the need for annual brain MRI monitoring to exclude brain lesion activity in clinically stable patients with low sNfL levels.

Background

Depression is a serious and co-morbid condition of MS. Up to 50% of individuals with MS experience clinically significant levels of depressive symptoms at any one time (Arnett et al., 2008). Depression and anxiety are especially high after diagnosis (Giordano et al., 2011; Kiropoulos et al., 2016) with 36% of individuals found to report high levels of depressive symptoms in the first years after diagnosis (Jensens et al., 2003). Cogntitive Behaviour Therapy (CBT) has shown to be effective in reducing symptoms of depression in those with MS (Kiropoulos et al., 2016) with the current study being the first RCT examining the effectiveness of a tailored cognitive behavioural therapy (CBT) intervention, compared to a supportive listening (SL) intervention, for depression in those who have been newly diagnosed with MS (within 5 years of having received a MS diagnosis).

Objectives

To assess efficacy of an early tailored CBT intervention, compared to SL, in producing significant and clinically meaningful reductions in: 1) depressive symptoms; 2) anxiety symptoms and 3) MS-related concerns (such as fatigue, sleep disturbance, pain impact). And to: 4) increase physical and mental health related quality of life, MS illness acceptance, social support, coping and resilience; and 5) to assess cost-effectiveness of providing the CBT intervention. An additional aim is to measure and examine changes in levels of cytokines before and after the interventions.

Methods

This is a two arm, parallel group, active comparator, assessor blinded RCT with the primary site being the Royal Melbourne Hospital. Recruitment is also being undertaken from three major MS clinics located in Melbourne, Victoria. 60 participants are being randomly allocated to a tailored CBT(n=30) or SL (n=30) intervention. 8 x 1 hour interventions will be delivered over 8 weeks by clinical psychologists for both treatment arms. Self-report and clinician data is and will be collected at pre, post and 3 mth follow up time points. Eligibility criteria includes mild to moderately depressed individuals newly diagnosed (within first 5 years of diagnosis) with MS. Exclusion criteria includes gross cognitive impairment; serious psychological disorder; delirium; undertaking psychological treatment for depression; unable to speak or read English.

Results

Preliminary results will be presented for the primary outcome which is the level of clinically significant change of 10 points or more on the BDI-2 at post therapy, secondary outcomes which are the level of depression at 3 mths and level of anxiety at post-assessment and tertiary outcomes which are the level of anxiety at 3 mths follow up, pain and fatigue impact, MS illness acceptance, sleep quality, coping, social support, resilience at post and 3 mth follow up.

Conclusions

Conclusions will be provided relating to the effectiveness of the CBT intervention in the treatment of depression in individuals newly diagnosed with MS.

Background

Therapeutic inertia (TI) is a worldwide phenomenon affecting physicians who manage patients with chronic conditions. Previous studies in Multiple Sclerosis (MS) showed TI affects 60 to 90% of neurologists and up to 25% of daily treatment decisions.

Objectives

To determine the most important factors and levels of attributes associated with treatment escalation in an international sample of neurologists with expertise in the management of patients with MS.

Methods

We conducted an international study comprised of 300 neurologists with expertise in MS from 20 countries (Europe: 59.4%, Asia/Australia: 18.3%, America: 22.3%). Participants were presented with 12 pairs of simulated MS patient profiles reflective of case scenarios encountered in clinical practice. Patient profiles included information on age, sex, previous MS history of relapses, MRI findings, desire for pregnancy, and other relevant details. We used disaggregated discrete choice experiments (a conjoint analysis), which is a standard technique used in economic research to estimate the weight of factors and attributes (e.g. categories) affecting physicians’ decisions when considering treatment selection by asking respondents to choose between pairs of options. In our study, participants were asked to select the ideal candidate (Patient A, B or neither) for treatment escalation (from first-line to second-line therapies- eg. Fingolimod, Cladribine, Monoclonal antibodies).

Results

Of 300 neurologists invited to participate, 229 (76.3%) completed the study. The mean age (SD) of study participants was 44 (±10) years. The mean (SD) number of MS patients seen per week by each neurologist was 18 (±16).

The top 3 factors (relative importance) associated with treatment escalation were: previous relapses (20%), EDSS (18%), and MRI activity (13%). Patient demographics and desire for pregnancy had a modest influence (<3%) in treatment escalation.

Participants were 13% less likely to escalate treatment for patients with EDSS >7.0 (compared to EDSS <6.0), whereas symptom severity during most recent relapse and higher number of MRI lesions at 1 year were each associated with 6% higher likelihood of treatment escalation.

We observed differences in the weight of factors associated with treatment escalation between MS specialists and non-specialists and participants practicing in European vs. non-European countries.

Conclusions

This is the first study applying a conjoint design to assess factors associated with treatment escalation and therapeutic inertia in neurologists caring for people living with MS. Our results provide critical information on factors influencing neurologists’ treatment decisions and should be applied to continuing medical education strategies.

Background

Disease-modifying therapies (DMT), which modify, mediate or suppress the immune system, are a major medication class for treating people with relapsing-onset multiple sclerosis (MS). However, our knowledge about these medications is largely limited to their short-term effects.

Objectives

To determine: 1) the impact of national-level DMT subsidy policy on DMT use and disability in people living with MS (PwMS); and 2) the long-term effects of DMT on disability (EDSS and MSSS) and quality of life (EQ5D5L utility score).

Methods

This project was an ecological, observational cohort study comparing populations in Australia and New Zealand with similar demographics, but markedly different levels of DMT use 10-20 years post-diagnosis. Differences between countries were assessed using standardized differences (Cohen’s d), phi coefficient and Cramer’s V. Associations were assessed with univariable and multivariable (mediation) linear regression models.

Results

We recruited 328 Australian participants, 93.9% of whom had been treated with DMT, and 256 New Zealand participants, 50.4% of whom had been treated with DMT. The Australian cohort had a longer median treatment duration (148 vs 0 months), greater proportion of disease course treated (86% vs 0%), and shorter time between diagnosis and first DMT (3 vs 24 months). The Australian cohort also had lower median EDSS (3.5 vs 4.0) and MSSS (3.05 vs 3.71), and higher quality of life (0.71 vs 0.65) at follow-up. In multivariable models, differences in DMT use significantly mediated the effect of country on disability and quality of life.

Conclusions

This large ecological study provides evidence for the impact of national level policy on DMT use and subsequent disability outcomes in PwMS. It also demonstrates that the protective effect of DMT may mediate the effect of national policy on disability progression and quality of life 10-20 years post-diagnosis in people with relapsing-onset MS.

Background

Longitudinal cognitive trajectories in MS are heterogenous and difficult to measure. Computerised tests designed to screen broad cognitive domains may be a reliable method to detect discrete trajectories of cognitive performance

Objectives

To validate a latent class model to identify trajectories of reaction time change in people with relapsing remitting MS (pwRRMS).

Methods

The MSReactor computerised cognitive battery is a self-administered, online set of reaction time tasks assessing psychomotor function (PsychoM), visual attention (VisAtt) and working memory (WorkingM). Participants completed both 6-monthly in-clinic testing and additional remote testing. Latent class analysis was used to model the longitudinal reaction times and identify discrete cognitive trajectories within the heterogeneous data. We applied a cross validation method to confirm the optimal models for all three reaction time tasks. Briefly, the cohort was split into training and test sets (50:50) and the mean root mean square error (RMSE) calculated for the difference between training and test trajectories calculated at each day of follow up, over 100 repetitions. To determine the minimum number of tests required to reliably classify an individual into a longitudinal trajectory the dataset for each task was reduced to 3, 4 and 5 tests per participant and classification compared to the complete dataset.

Results

We included 478 pwRRMS who had completed at least 3 MSReactor tests over a minimum of 30 days follow up. In total, 3846 individual tests were included in each model (median tests/participant=5 (range 3-332), mean follow up of 774 +- 359.5 days). Three latent classes were identified for each task, with the PsychoM task identifying a group of pwRRMS with a mean predicted trajectory of slowing reaction times. In validation, the PsychoM task was the most consistent with the smallest RMSE for each of the 3 classes (68 milliseconds (ms), 95%CI 59-77ms; 61ms, 95% CI 50-72ms and 16ms, 95% CI 14-18ms) followed by the VisAtt task (RMSE = 114ms, 95ms and 29ms) and WorkingM task (RMSE = 137ms, 138ms and 46ms). Reduced datasets of 3, 4 and 5 tests per participant in the PsychoM task were able to classify participants into the trajectories identified in the full dataset model, with 83%, 86% and 90% accuracy respectively.

Conclusions

Latent class modelling of longitudinal reaction times collected with MSReactor was able to detect discrete trajectories of cognitive performance. The PsychoM task latent class model identified a group of RRMS with a mean predicted slowing of reaction times and was the most consistent model in cross validation. Performing the modelling on just 3, 4 or 5 tests per participant was highly accurate in defining latent trajectories, giving the battery clinical utility where multiple years of follow up may not be realistic.

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

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.

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.

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 4^th 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.

Background

Disease activity has been investigated in pregnant women with RRMS treated with low-efficacy or no therapy. How newer, more efficacious therapies affect relapse and disability progression risk after pregnancy remains understudied.

Objectives

To describe disease activity in a modern pregnancy cohort contrasted with historical cohorts. To determine the predictors of postpartum relapse and the predictors of six-month confirmed disability progression events in a contemporary pregnancy cohort.

Methods

Data were obtained from the MSBase Registry. Term/preterm pregnancies conceived from 2011-2019 (modern cohort) were compared with those conceived between 2005-2010 and pre-2005. Annualised relapse rates (ARR) were calculated for each pregnancy trimester and 12 months either side. Predictors of time-to-relapse postpartum (1^st 3 months) and time to 6-month confirmed disability progression event were determined with clustered Cox regression analyses. Breastfeeding duration and time to DMT reinitiation were modelled as time-varying covariates.

Results

We included 1640 pregnancies from 1452 women (modern cohort). Disease-modifying therapy (DMT) used in the year before conception included interferon-beta (n=597), natalizumab (n=219) and fingolimod (n=147). Continuation of DMT up to conception increased over time (31% pre-2005 vs 54% modern cohort). Preconception ARR decreased across epochs (pre-2005: 0·58 [95% CI 0·49-0·70]; 2005-2010: 0·40 [95% CI 0·36-0·45]; modern: 0·29 [95% CI 0·27-0·32]). In all epochs, ARR decreased during pregnancy to reach similar troughs in the 3^rd trimester, and rebounded in the 1^st 3-months postpartum. Preconception use of high-efficacy DMT predicted early postpartum relapse (hazard ratio (HR) 2.1 [1.4-3.1]); although those on no DMT were also at risk of postpartum relapse, relative to women on low-efficacy DMT (HR 2.7 [1.2-5.9]). Conception EDSS ≥2, higher preconception and in-pregnancy ARR were also risk factors. DMT reinitiation, particularly of high-efficacy DMT (HR 0.17 [0.07-0.38]), was protective against postpartum relapse. Women who breastfed were less likely to relapse (HR 0.63 [0.42-0.94]). 4.5% of modern pregnancies had confirmed disability progression after delivery. This was predicted by higher pregnancy and postpartum ARR, with postpartum ARR remaining independently predictive in multivariable analysis (HR 1.5 [1.2-2.0]).

Conclusions

The early postpartum period remains a period of vulnerability for disease rebound in women with MS in the modern era. Early DMT reinitiation, particularly with high-efficacy treatment, is protective against postpartum relapse. Confirmed disability progression events after pregnnacy are uncommon in the modern era. Relapse activity is the key driver of these events.