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.

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.

Background

Cognitive impairment (CI) affects nearly 30% of paediatric patients with Multiple Sclerosis (MS) and has a negative impact on school performance and participation in social activities. This study is a re-appraisal of cognitive functioning and socio-professional attainment in adulthood in an Italian cohort of paediatric MS patients after 10 years from baseline neuropsychological assessment.

Objectives

To re-assess cognitive performance and its impact on socio-professional attainment in our cohort of paediatric MS patients after 10 years from baseline evaluation and to determine predictors of the individual outcomes.

Methods

Sixty-three paediatric patients were assessed at baseline and 48 followed-up after five years. To date, 31 out of these 48 patients (17 females, mean age 27.9±2.5 years, mean EDSS 1.7±1.6) were reassessed on an extensive neuropsychological battery and compared with a matched group of 31 healthy controls. CI was defined as the failure of > 2 tests. Socio-professional attainment was evaluated on the Work and Social Assessment Scale (WSAS). Predictors of CI and WSAS score were assessed through multivariable logistic and linear models.

Results

After a mean follow-up of 12.5±2.3 years, 15 (54%) subjects were classified as cognitively impaired. Patients with CI compared with those cognitively preserved at follow-up had higher Expanded Disability Status Scale (EDSS) score (1.9±1.4 vs 1.0±0.7; p = 0.046), lower baseline intelligence quotient (IQ) (86.2±23.8 vs 103.6±14.7; p = 0.025) and were less frequently treated with disease modifying therapy (DMT) at baseline [6 (35.3%) vs 11 (78.6%); p = 0.016]. In the regression model, CI after 10 years was related to lower IQ (OR 0.93, 95% CI 0.87-0.99, p = 0. 027) and absence of DMT at baseline assessment (OR 17.78 95%; 1.72-183.65, p = 0.017).

Baseline predictors of worse socio-professional attainment on the WSAS in adulthood were CI (B=6.3, p=0.016), higher EDSS (B=2.2, p=0.023) and higher age at onset (B=0.6, p=0.041). As for 10-year correlates, only CI was associated to poor functional outcome (B=5.2, p=0.006).

Conclusions

Complete data collection is ongoing; available findings to date show that in paediatric onset subjects CI remains significant in adulthood, is related to lower cognitive reserve, higher levels of neurological impairment and delay in DMT initiation. Moreover, CI plays a key role in predicting the subject social performance and professional outcome. Early treatment and promotion of strategies aimed at enhancing cognitive reserve are recommended in paediatric patients with MS.

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.

Background

Natalizumab 300 mg every 4 weeks (Q4W) is an effective therapy for relapsing-remitting multiple sclerosis (MS) but is also associated with increased risk of progressive multifocal leukoencephalopathy (PML) in anti–JC virus seropositive patients. Analysis of the TOUCH Prescribing Program safety database showed that natalizumab extended interval dosing (EID; average dosing interval approximately 6 weeks) is associated with lower risk of PML than Q4W dosing. Previous analysis of TYSABRI Observational Program (TOP) data showed no difference in relapse outcomes for patients on Q4W and every-6-week (Q6W) dosing. Comparative disability outcome data in well-matched real-world populations are lacking.

Objectives

Compare relapse and disability outcomes in propensity-score (PS)–matched TOP patients who switched to Q6W dosing with outcomes in patients who remained on Q4W dosing.

Methods

Intentional dosing data collected in TOP as of November 2019 were used to identify patients with ≥1 year of Q4W dosing who remained on Q4W or switched to Q6W dosing. Patients with dosing intervals ≥12 weeks or <3 weeks were excluded. Patients with similar exposures were PS-matched 1:1 with age, sex, Expanded Disability Status Scale score, time from MS onset, exposure duration, and relapse activity as covariates. Between-group comparisons were made for the post-switch follow-up period for Q6W patients and the matching time period for Q4W patients. Adjusted relapse rates (ARRs) were calculated using negative binomial regression with robust standard error estimation. Hazard ratios (HRs) for time to first relapse and 24-week confirmed disability worsening (CDW) were estimated with Kaplan-Meier and Cox methods.

Results

The analysis included 236 matched pairs of Q6W and Q4W patients. Mean (SD) follow-up times for Q6W and Q4W patients were 2.00 (1.30) and 1.89 (1.15) years, respectively. ARRs (0.146 vs 0.139; P=0.796), time to first relapse (HR [95% CI] 1.078 [0.723–1.608]; P=0.711), and time to CDW (HR [95% CI] 0.749 [0.270–2.074]; P=0.578) did not differ significantly for Q6W and Q4W patients.

Conclusions

Relapse and disability outcomes in TOP were similar for PS-matched patients who switched to Q6W or remained on Q4W dosing. These results are consistent with prior matched and unmatched analyses in real-world settings and underscore the need for the ongoing, prospective, randomized efficacy trial of natalizumab Q6W vs Q4W dosing (NOVA, clinicaltrials.gov NCT03689972).

The TOP study was supported by Biogen.

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.

Background

Natalizumab and fingolimod are indicated in the EU for patients with rapidly evolving severe relapsing-remitting multiple sclerosis (RES RRMS; ≥2 relapses in 1 year and ≥1 gadolinium-enhancing lesions or increased T2 lesion numbers on MRI) or highly active RRMS. Patients with RRMS may also receive first-line therapies (interferon beta, glatiramer acetate, dimethyl fumarate, or teriflunomide; collectively BRACETD). Effectiveness comparisons of therapies in patients with RES RRMS are lacking.

Objectives

To compare the clinical effectiveness of natalizumab, fingolimod, and BRACETD in patients with RES RRMS in real-world settings.

Methods

Data from the MSBase registry as of August 2019 were used. Adults with RRMS, ≥2 relapses in the past 12 months, and available Expanded Disability Status Scale scores at baseline (BL) and on therapy were included. At index date, patients were treatment naive or had switched from BRACETD to natalizumab, fingolimod, or another BRACETD. Patients were propensity score matched 1:1:1 based on BL demographic and clinical variables. Annualized relapse rates (ARRs) were compared using a generalised estimating equation Poisson regression model. Other outcomes (time to first relapse, 6-month confirmed disability worsening [CDW], and 6-month confirmed disability improvement [CDI]) were analysed using Cox marginal regression models.

Results

Matched treatment groups included 721 triplets of patients with mean follow-up of approximately 3 years. In each group, 23.3–23.9% of patients were treatment naïve. ARR (95% CI) was lowest with natalizumab (0.18 [0.17–0.20]) followed by fingolimod (0.29 [0.26–0.31]) and BRACETD (0.39 [0.37–0.42]; P<0.001 for all comparisons); rate ratio (95% CI) vs BRACETD was 0.46 (0.42–0.53) for natalizumab and 0.72 (0.65–0.80) for fingolimod. Risk of first relapse was lower with natalizumab vs fingolimod (hazard ratio [HR] [95% CI], 0.63 [0.53–0.74]) or BRACETD (0.41 [0.36–0.48]; P<0.001 for both) and with fingolimod vs BRACETD (0.66 [0.57–0.76]; P<0.001). No differences in CDW were observed. CDI was more likely with natalizumab than with fingolimod (HR [95% CI], 1.25 [1.01–1.55]; P=0.047) or BRACETD (1.46 [1.16–1.85]; P=0.002). CDI was not significantly different between fingolimod and BRACETD (HR [95% CI], 1.17 [0.91–1.50]; P=0.209).

Conclusions

In this large cohort of patients with RES RRMS treated in real-world settings, natalizumab was more effective than fingolimod or BRACETD at reducing relapses. Natalizumab patients were also 25% and 46% more likely to exhibit CDI than fingolimod and BRACETD patients, respectively.

This study was supported by Biogen International (Zug, Switzerland).

Background

MSProDiscuss^TM is a validated, physician-completed tool aimed at facilitating physician–patient conversation on signs of progression in multiple sclerosis (MS). A set of weighted questions on relapses, symptoms and their impacts as experienced by the patient generate a traffic light system output to aid the discussion. The tool is available online at www.msprodiscuss.com.

Objectives

Evaluate the usability and usefulness of MSProDiscuss in discussing disease progression in daily clinical practice.

Methods

An online qualitative survey consisting of individual questionnaires completed by healthcare professionals (HCPs) after using MSProDiscuss in patient consultations and a final questionnaire to capture overall experience on the tool was conducted in 34 countries. General feedback and recommendations for improving the tool were also collected.

Results

In total, 301 HCPs participated in the survey. The HCPs first completed individual questionnaires after using MSProDiscuss on 6974 MS patients and then a final questionnaire. In 97% (initial questionnaire, i) and 98% (final questionnaire, f) of the time MSProDiscuss was used, the time taken to complete the tool was considered satisfactory (1-4min). The questions were found to be comprehensible in 94% (i) to 97% (f) of cases, and HCPs are willing to use the tool again in the same patient 91% (i) of the time. MSProDiscuss was also useful in discussing MS symptoms and its impact on daily activities (88% i / 92% f) and cognitive function (79% both i and f) and in discussing progression in general (88% i / 90% f).

Moreover, in the final questionnaire, 95% agreed that the questions were similar to those asked by a HCP in a regular consultation. MSProDiscuss was also found to be helpful for understanding the impact of MS symptoms on daily activities (91%) and cognitive function (80%). Overall, 92% of the HCPs would recommend MSProDiscuss to a colleague; 92% think that it is feasible and 86% are willing to integrate MSProDiscuss into their clinical practice. Key recommendations were to allow for longitudinal follow-up, expand on cognitive assessments, and provide a patient-completed version. These have been considered for implementation in the updated version of MSProDiscuss.

Conclusions

The survey results established MSProDiscuss as useful and easy to use tool to facilitate patient-physician discussion of MS progression by structured capturing of patient clinical profile. Most HCPs were willing to integrate MSProDiscuss into their daily clinical practice.

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.

Background

Unemployment rates can be high among patients with multiple sclerosis (MS), and a return to work after unemployment can be difficult, highlighting the importance of treatment in preventing a departure from the workforce due to MS. Natalizumab is a highly effective treatment for patients with relapsing-remitting MS (RRMS) and was associated with positive employment outcomes in real-world studies.

Objectives

To evaluate changes in employment status in RRMS patients treated with natalizumab in the TYSABRI Observational Program (TOP), a large observational study assessing the long-term safety and effectiveness of natalizumab.

Methods

This retrospective analysis included patients aged ≤65 years at TOP enrolment (i.e., baseline [BL]) who were surveyed on their employment status in the year before natalizumab initiation and in the period since treatment initiation (N=2004). Multivariate logistic regression tested the association between BL characteristics and employment outcomes.

Results

At BL, patients had a mean (standard deviation [SD]) Expanded Disability Status Scale (EDSS) score of 3.5 (1.5). At the survey, patients had a mean (SD) of 5.5 (3.3) years of natalizumab treatment. Survey responses indicated that in the year before natalizumab initiation, 1107 patients (55.2%) were working; 814 patients (40.6%) were working full time, 53 (2.6%) were working part time due to MS, 265 (13.2%) were not working due to MS, and 240 (12.0%) and 632 (31.5%) were working part time or not at all, respectively, for other reasons. After natalizumab initiation, 861 patients (43.0%) improved (1.3%) or maintained (41.6%) their employment level, whereas 170 (8.5%) experienced a decline in employment level due to MS and 256 (12.8%) remained unemployed due to MS. Significant predictors of improving/maintaining employment status were younger age (adjusted odds ratio [aOR]: 0.756; P=0.005), lower BL EDSS score (aOR: 0.747; P<0.001), and fewer relapses in the year before natalizumab initiation (aOR: 0.829; P=0.042), but did not include sex, prior therapy use, or RRMS duration.

Conclusions

Of patients who were working prior to natalizumab initiation, 77.0% maintained or improved their employment level with an average follow up of 5.5 years. Overall, favourable outcomes were predicted by younger age and less BL disease activity, supporting the importance of natalizumab initiation early in the disease course to help prevent patients from leaving the workforce due to MS.

The TOP study is funded by Biogen. Biogen funded the analyses and writing support for this abstract. Writing support was provided by Ashfield Healthcare Communications (Middletown, CT, USA).