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.

Background

Recent US estimates suggest that the prevalence of multiple sclerosis (MS) is nearly 3 times higher in women, many of childbearing age. Oral delayed-release dimethyl fumarate (DMF) has demonstrated a favorable benefit-risk profile in trials and post-marketing surveillance. DMF should be used in pregnant women with MS only if the potential benefit justifies the potential risk to the fetus.

Objectives

To provide pregnancy outcomes and DMF exposure data as of 08 April 2020 in women with MS treated with DMF in an ongoing prospective international registry (NCT01911767, TecGistry).

Methods

Women exposed to DMF from the first day of their last menstrual period before conception or during pregnancy were evaluated. Data were obtained at enrolment, 6−7 months of gestation, 4 weeks after estimated due date, and 4, 12 and 52 weeks after birth. As reported previously, outcomes included live births, pregnancy loss, ectopic/molar pregnancies, birth defects and anomalies, and infant or maternal death after delivery. Gestational weight was classified by percentile (<10^th, 10^th−90^th, >90^th) based on standardized growth charts.

Results

As of 08 April 2020, 345 patients were enrolled, with a median age of 32 years. Median gestational week at first exposure to DMF was 1 (range: 0, 13) and at enrollment was 9 (0, 39.3). Median (range) duration of fetal DMF exposure duration was 5 (0, 40) weeks. Among discontinuations, one was due to a serious AE. Of the known outcomes, 277 were live births (122 with 52 weeks of follow-up), 19 fetal losses including 1 molar and 1 ectopic pregnancy resulting in spontaneous abortions. One neonatal death and no maternal deaths were reported. Of 274 infants of known gestational age, 249 (91%) were full term, and 25 (9%) premature (<37 weeks). Gestational weight data were available for 232 infants, of whom 26 (11%) were small, 190 (82%) appropriate, and 16 (7%) large. Overall, 8 infants had adjudicator-confirmed birth defects, including ventricular septal defect, congenital hydronephrosis, ureteral duplication, pyloric stenosis, transposition of the great vessels, unilateral developmental dysplasia of the hip, and 1 premature infant with multiple birth defects.

Conclusions

The pregnancy outcome frequencies observed in this updated analysis were consistent with previous reports and did not exceed those seen in the MS and general populations. No additional safety signals were identified.

Supported by: Biogen