Natalizumab, Fingolimod and Dimethyl Fumarate Use and Pregnancy-Related Relapse and Disability in Women With Multiple Sclerosis

To investigate pregnancy-related disease activity in a contemporary multiple sclerosis (MS) cohort

Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis.

IMPORTANCE: Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressive MS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition. OBJECTIVE: To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition. DESIGN, SETTING, AND PARTICIPANTS: Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remitting MS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years' follow-up. EXPOSURES: The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017). MAIN OUTCOME AND MEASURE: Conversion to objectively defined secondary progressive MS. RESULTS: Of the 1555 patients, 1123 were female (mean baseline age, 35 years [SD, 10]). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressive MS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P < .001; 5-year absolute risk, 12% [49 of 407] vs 27% [58 of 213]; median follow-up, 7.6 years [IQR, 5.8-9.6]), as did fingolimod (HR, 0.37; 95% CI, 0.22-0.62; P < .001; 5-year absolute risk, 7% [6 of 85] vs 32% [56 of 174]; median follow-up, 4.5 years [IQR, 4.3-5.1]); natalizumab (HR, 0.61; 95% CI, 0.43-0.86; P = .005; 5-year absolute risk, 19% [16 of 82] vs 38% [62 of 164]; median follow-up, 4.9 years [IQR, 4.4-5.8]); and alemtuzumab (HR, 0.52; 95% CI, 0.32-0.85; P = .009; 5-year absolute risk, 10% [4 of 44] vs 25% [23 of 92]; median follow-up, 7.4 years [IQR, 6.0-8.6]). Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR, 0.66; 95% CI, 0.44-0.99; P = .046); 5-year absolute risk, 7% [16 of 235] vs 12% [46 of 380]; median follow-up, 5.8 years [IQR, 4.7-8.0]). The probability of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset vs later (HR, 0.77; 95% CI, 0.61-0.98; P = .03; 5-year absolute risk, 3% [4 of 120] vs 6% [2 of 38]; median follow-up, 13.4 years [IQR, 11-18.1]). When glatiramer acetate or interferon beta were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years vs later, the HR was 0.76 (95% CI, 0.66-0.88; P < .001; 5-year absolute risk, 8% [25 of 307] vs 14% [46 of 331], median follow-up, 5.3 years [IQR], 4.6-6.1). CONCLUSIONS AND RELEVANCE: Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies' risks, may help inform decisions about DMT selection.This study was financially supported by National Health and Medical Research Council of Australia (fellowships 1140766 and 1080518, project grants 1129189 and 1083539), the University of Melbourne (Faculty of Medicine, Dentistry and Health Sciences research fellowship), a Next Generation Fellowship funded by the Grand Charity of the Freemason’s (recipient JWLB), and the MSBase 2017 Fellowship (recipient JWLB). Alemtuzumab studies done in Cambridge were supported by the NIHR Cambridge Biomedical Research Centre and the MS Society UK

International Development of the Patient-Reported Outcome Indices for Multiple Sclerosis (PRIMUS)

Background: The Patient-Reported Indices for Multiple Sclerosis (PRIMUS) comprises a suite of three scales for assessing symptoms, activity limitations, and quality of life in multiple sclerosis (MS). It was developed in the UK and has been shown to have excellent psychometric properties. This study describes the adaptation of eight language versions for Canadian English, Canadian French, French, German, Italian, Spanish, Swedish, and US English. Methods: The PRIMUS was translated using the dual-panel process. Cognitive debriefing interviews conducted with MS patients assessed face and content validity. Psychometric and scaling properties were assessed via a two-administration postal survey conducted in each country involving the PRIMUS, the Nottingham Health Profile (NHP), the Unidimensional Fatigue Impact Scale (U-FIS), and demographic questions. Results: Cognitive debriefing interviews demonstrated the acceptability of the new language versions. Analysis of survey data showed that the new language versions of the three PRIMUS scales were unidimensional (as indicated by fit to the Rasch model) and that they had good internal consistency and reproducibility. PRIMUS scale scores correlated as expected with those on the NHP and the U-FIS. The scales in all countries were able to discriminate between groups of patients on the basis of their self-reported MS severity, general health, and employment status. Conclusions: The PRIMUS was successfully adapted into eight new languages. Most of the tests showed the PRIMUS to have good unidimensionality and to have good internal consistency, reproducibility, and construct validity. The measure is now available for use in clinical studies and trials involving these countries and the UK. Further work is required to assess the measure's responsiveness

International Development of the Unidimensional Fatigue Impact Scale (U-FIS)

Objective: The 22-item Unidimensional Fatigue Impact Scale (U-FIS) provides an index of the impact of fatigue on patients with multiple sclerosis (MS). The objective is to produce eight new language versions of the U-FIS: Canadian-English, Canadian-French, French, German, Italian, Spanish, Swedish, and US-English. Methods: The U-FIS was translated via two translation panels. Cognitive debriefing interviews conducted with patients in each country assessed face and content validity. Scaling and psychometric properties were assessed via survey data with patients in each country completing the U-FIS, Nottingham Health Profile (NHP), and demographic questions. Results: Cognitive debriefing interviews demonstrated U-FIS acceptability. Analysis of postal survey data showed all new language versions to be unidimensional. Reliability was high, with test-retest correlations and internal-consistency coefficients exceeding 0.85. Initial evidence of validity was provided by moderate to high correlations with NHP scales. The U-FIS was able to discriminate between groups based on employment status, perceived MS severity, and general health. Conclusion: The U-FIS is a practical new measure of the impact of fatigue. It was successfully adapted into eight new languages to broaden availability for researchers. Psychometric analyses indicated that the new language versions were unidimensional and reproducible with promising construct validity

Discontinuing disease-modifying therapy in MS after a prolonged relapse-free period: A propensity score-matched study

Background Discontinuation of injectable diseasemodifying therapy (DMT) for multiple sclerosis (MS) after a long period of relapse freedom is frequently considered, but data on post-cessation disease course are lacking. Objectives (1) To compare time to first relapse and disability progression among 'DMT stoppers' and propensity-score matched 'DMT stayers' in the MSBase Registry; (2) To identify predictors of time to first relapse and disability progression in DMT stoppers. Methods Inclusion criteria for DMT stoppers were: age =18 years; no relapses for =5 years at DMT discontinuation; follow-up for =3 years after stopping DMT; not restarting DMT for =3 months after discontinuation. DMT stayers were required to have no relapses for =5 years at baseline, and were propensityscore matched to stoppers for age, sex, disability (Expanded Disability Status Score), disease duration and time on treatment. Relapse and disability progression events in matched stoppers and stayers were compared using a marginal Cox model. Predictors of first relapse and disability progression among DMT stoppers were investigated using a Cox proportional hazards model. Results Time to first relapse among 485 DMT stoppers and 854 stayers was similar (adjusted HR, aHR=1.07, 95% CI 0.84 to 1.37; p=0.584), while time to confirmed disability progression was significantly shorter among DMT stoppers than stayers (aHR=1.47, 95% CI 1.18 to 1.84, p=0.001). The difference in hazards of progression was due mainly to patients who had not experienced disability progression in the prebaseline treatment period. Conclusions Patients with MS who discontinued injectable DMT after a long period of relapse freedom had a similar relapse rate as propensity score-matched patients who continued on DMT, but higher hazard for disability progression

Switching to natalizumab or fingolimod in multiple sclerosis: Comparative effectiveness and effect of pre-switch disease activity

© 2022Background: Patients with relapsing-remitting multiple sclerosis (RRMS) who experience relapses on a first-line therapy (interferon, glatiramer acetate, dimethyl fumarate, or teriflunomide; collectively, “BRACETD”) often switch to another therapy, including natalizumab or fingolimod. Here we compare the effectiveness of switching from a first-line therapy to natalizumab or fingolimod after ≥1 relapse. Methods: Data collected prospectively in the MSBase Registry, a global, longitudinal, observational registry, were extracted on February 6, 2018. Included patients were adults with RRMS with ≥1 relapse on BRACETD therapy in the year before switching to natalizumab or fingolimod. Included patients received natalizumab or fingolimod for ≥3 months after the switch. Results: Following 1:1 propensity score matching, 1000 natalizumab patients were matched to 1000 fingolimod patients. Mean (standard deviation) follow-up time was 3.02 (2.06) years after switching to natalizumab and 2.58 (1.64) years after switching to fingolimod. Natalizumab recipients had significantly lower annualized relapse rate (relative risk=0.66; 95% confidence interval [CI], 0.59–0.74), lower risk of first relapse (hazard ratio [HR]=0.69; 95% CI, 0.60–0.80), and higher confirmed disability improvement (HR=1.27; 95% CI, 1.03–1.57) than fingolimod recipients. No difference in confirmed disability worsening was observed. Conclusions: Patients with RRMS switching from BRACETD demonstrated better outcomes with natalizumab than with fingolimod

Predictors of relapse and disability progression in MS patients who discontinue disease-modifying therapy

Background: Discontinuation of disease-modifying therapies (DMTs) for MS is common. MSBase, a large global observational registry, affords a unique opportunity to investigate predictors of \u2018post-DMT\u2019 relapses and confirmed disability progression (CDP) in a diverse group of patients exposed to different DMTs. Materials/methods: Main inclusion criteria: clinician-confirmed MS diagnosis (2010 McDonald criteria); age 65 18 at index DMT start; 6512 months on index DMT prior to discontinuation; 6524 months of follow-up post-discontinuation; did not restart DMT for 656 months. Predictors of time to first relapse and 3-month CDP were analyzed using Cox proportional hazards regression adjusted for age, gender, baseline EDSS, EDSS stability and relapse-free period for 651 year prior to discontinuation, calendar epoch, index DMT and reason for discontinuation. Results: 4842 patients (74.2% female) from 20 MSBase Centers met our inclusion criteria. 3556 (73%) discontinued one of IFN\u3b2 preparations, 849 (18%) - glatiramer acetate, 308 (6%) - natalizumab and 129 (3%) \u2013 fingolimod; other DMTs were excluded because too few records were available. Overall post-discontinuation annualized relapse rate (95% CI) was 0.224 (0.219, 0.229) and CDP rate was 8.23 (7.72, 8.76) per 100 person-years. Risk of post-DMT relapse was higher in younger patients, female patients, those with moderate disability and a relapse within 1 year of discontinuation. Hazard of CDP increased with increasing disability at baseline and disease progression within 3 years prior to stopping DMT. Of all the DMTs, only natalizumab was associated with increased risk of both post-DMT relapse and CDP. Conclusions: Knowledge of post-DMT relapse and disability progression rates and predictors of post-DMT disease activity allows for a more informed discussion of DMT discontinuation in those patients who are considering this option

Fingolimod after natalizumab and the risk of short-term relapse

OBJECTIVE: To determine early risk of relapse after switch from natalizumab to fingolimod; to compare the switch experience to that in patients switching from interferon-β/glatiramer acetate (IFN-β/GA) and those previously treatment naive; and to determine predictors of time to first relapse on fingolimod. METHODS: Data were obtained from the MSBase Registry. Relapse rates (RRs) for each patient group were compared using adjusted negative binomial regression. Survival analyses coupled with adjusted Cox regression were used to model predictors of time to first relapse on fingolimod. RESULTS: A total of 536 patients (natalizumab-fingolimod [n = 89]; IFN-β/GA-fingolimod [n = 350]; naive-fingolimod [n = 97]) were followed up for a median 10 months. In the natalizumab-fingolimod group, there was a small increase in RR on fingolimod (annualized RR [ARR] 0.38) relative to natalizumab (ARR 0.26; p = 0.002). RRs were generally low across all patient groups in the first 9 months on fingolimod (RR 0.001–0.13). However, 30% of patients with disease activity on natalizumab relapsed within the first 6 months on fingolimod. Independent predictors of time to first relapse on fingolimod were the number of relapses in the prior 6 months (hazard ratio [HR] 1.59 per relapse; p = 0.002) and a gap in treatment of 2–4 months compared to no gap (HR 2.10; p = 0.041). CONCLUSIONS: RRs after switch to fingolimod were low in all patient groups. The strongest predictor of relapse on fingolimod was prior relapse activity. Based on our data, we recommend a maximum 2-month treatment gap for switches to fingolimod to decrease the hazard of relapse. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that RRs are not higher in patients with multiple sclerosis switching to fingolimod from natalizumab compared to those patients switching to fingolimod from other therapies

Increasing age at disability milestones among MS patients in the MSBase Registry.

The more recent MSBase enrollees in each of the mild-to-moderate disability strata were significantly older than earlier enrollees. Possible explanations for this phenomenon are discussed