Marzena Pedrini

Introduction: Vascular comorbidities (VCM) are common in patients with multiple sclerosis (MS). VCM are associated with increased disease activity and disability progression, but long-term clinical follow-up data in larger cohorts is limited.

Objectives/Aims: To investigate whether VCM are associated with relapse rates or disability progression in relapsing-remitting MS (RRMS).

Methods: We analysed longitudinal data from MSBase, an international prospective registry of patients with MS. Adults with RRMS, no relapses over the preceding year and no commencement or switching of disease-modifying therapy (DMT) were identified from 2015–2017. Included participants were followed up for 5 years. Baseline VCM (hypertension, hyperlipidaemia, diabetes, ischaemic heart disease) were analysed as individual VCM and as cumulative count of VCM (0/1/2+). Poisson and Cox regression were used to investigate the association between VCM, relapse rates and disability progression over 5 years of follow-up, respectively, with models adjusted for age, sex, disease duration and baseline DMT. As a sensitivity analysis, we analysed a subgroup of 18 sites participating in the MSBase Safety substudy with more complete registry data.

Results: 42185 participants were followed-up over 5 years. The mean age was 44.4 years (SD 12.7), and 72.3% were female. Recorded VCM were hypertension (n=912), diabetes (n=451), hyperlipidaemia (n=325) and ischaemic heart disease (n=186). Median Expanded Disability Status Scale (EDSS) was 2.0 at baseline (IQR 1.0–4.0) and 2.5 at 5 years (IQR 1.5–5.5).

7454 participants (17.7%) had 1 or more relapses over 5 years. Hypertension was associated with increased relapse rate (IRR [95% CI] 1.75 [1.55–1.99]; p<0.001), as were hyperlipidaemia (IRR 1.93 [1.58–2.35]; p<0.001) and diabetes (IRR 1.89 [1.61–2.22]; p<0.001), but not ischaemic heart disease (IRR 1.28 [0.96–1.70]; p=0.09). The relapse rate was increased in those with 1 VCM (IRR 1.81 [1.64–2.00]; p<0.001) and 2 VCM+ (IRR 1.74 [1.36–2.23]; p<0.001), compared to those with no VCM. In the sensitivity analysis, hypertension (IRR 1.20 [1.01–1.42]; p=0.04), diabetes (IRR 1.74 [1.44–2.09]; p<0.001) and 1 VCM (IRR 1.37 [1.20–1.57]; p<0.001) were also associated with increased relapse rates. VCM were not associated with EDSS worsening.

Conclusion: Vascular risk factors are associated with increased disease activity over 5 years in RRMS.

Introduction: Family planning is an integral aspect in the care of women with multiple sclerosis (MS). As disease-modifying therapy (DMT) discontinuation may increase relapse activity, treatment benefits need to be carefully balanced against the risk to the unborn. Ocrelizumab may be a suitable option for women with MS who are planning to conceive, but real-world data on disease activity during pregnancy and postpartum versus other DMTs are scarce.

Objectives/Aims: To describe relapse activity in women with MS before, during and after pregnancy treated with ocrelizumab versus other DMTs.
Methods: Pregnancies in women with MS recorded in MSBase since 2011 up to 1st March 2023 treated with ocrelizumab (OCR), natalizumab (NAT), dimethyl fumarate (DMF) or low-efficacy DMT (interferon-beta, glatiramer acetate) before pregnancy were included. Annualised relapse rates (ARR) were calculated per three-month period for the one-year preconception, during and after pregnancy.

Results: A total of 1654 women with 1901 pregnancies were included (OCR, n=58; NAT, n=398; DMF, n=156; low-efficacy DMT, n=1289). For NAT, use was further subset into continuation into pregnancy third trimester with early (⩽1 month) postpartum re-initiation (NAT-E, n=77)), and cessation prior to four-weeks gestation with late postpartum re-initiation (NAT-L, n=79). One-year preconception ARR [95% CI] was 0.15 [0.06-0.30] for OCR; 0.11 [0.08-0.15] for NAT; 0.12 [0.07-0.19] for DMF; and 0.22 [0.19-0.25] for low-efficacy DMT. During pregnancy, ARR [95% CI] was 0 [0-0.09] for OCR; 0.04 [0-0.13] for NAT-E; 0.34 [0.20-0.52] for NAT-L; 0.12 [0.07-0.21] for DMF; and 0.12 [0.10-0.14] for low-efficacy DMT. Postpartum ARR [95% CI] was 0.11 [0.02-0.33] for OCR; 0.11 [0.03-0.28] for NAT-E; 0.77 [0.52-1.11] for NAT-L; 0.41 [0.28-0.59] for DMF; and 0.43 [0.38-0.49] for low-efficacy DMT. Three women treated with ocrelizumab preconception experienced a postpartum relapse, two of which occurred prior to ocrelizumab re-initiation; none of these women had relapses pre-conception or during pregnancy.

Conclusion: This real-world analysis suggests that women with MS receiving ocrelizumab pre-conception are likely at low risk for within-pregnancy relapse and not at increased risk of postpartum relapses. However, treatment pauses after birth may increase relapse risk. Further data including predictors of postpartum relapses are warranted to ensure optimal care to women with MS and their infants.

Introduction: DNA methylation at CpG sites is an epigenetic mechanism that can influence gene expression. Epigenome-wide association studies (EWASs) of immune cells have implicated differential methylation in Multiple Sclerosis MS. Furthermore, differences in global DNA methylation profiles have been demonstrated after treatment with various disease modifying therapies such as interferon beta and dimethyl fumarate. Whether or not these changes can be used to predict response to treatment at baseline is unknown.
Objectives/Aims: The objective of this study was to assess if there are changes in global DNA methylation that can predict response to cladribine tablets in people with MS (pwMS).
Methods: Whole blood DNA was collected from a subset of the prospectively followed cohort from the CLOBAS study which is a phase IV, multicentre, open label, six-year study of cladribine tablets for pwMS. Participants were considered non-responders if they had a clinical relapse or new MRI activity between three- and 30-months post first dose of cladribine tablets. Bisulfite converted DNA was hybridised to Illumina Infinium EPIC v2 arrays and analysed using the ChAMP R package. GLMNet was used to select meaningful features of baseline DNA methylation that could discriminate between responders and non-responders.
Results: Fifteen of 102 participants were considered non-responders after 30 months of cladribine tablet use. The single most significant feature was cg15041948, which maps to the transcription start site of the GPBP1 gene, which codes for the Vasculin protein. This CpG has a good ability to discriminate between responders and non-responders (Area Under the Curve (AUC) = 0.78). Using the top 28 features identified by GLMNet, the ability to discriminate between responders and non-responders was perfect (AUC=1).
Conclusion: We are able to use global DNA methylation profiles to discriminate between responders and non-responders to cladribine treatment. Low numbers mean results should be interpreted with caution, however, the CLOBAS study is a six-year prospective cohort, therefore, longer term follow studies will follow.