B. Taylor
University of Tasmania Menzies Institute for Medical ResearchAuthor Of 2 Presentations
FC04.02 - Effects of natalizumab on patient-reported MS outcomes using prospective data from the Australian MS longitudinal study
Abstract
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.
PS08.03 - Deconvolution of epigenetic profiles reveals blood cell-specific pathways associated with early stage Multiple Sclerosis in the AusImmune Study
Abstract
Background
Genomic DNA methylation is a modifiable epigenetic mechanism that exhibits wide-spread variation among blood cell types. Methylation can influence disease phenotypes via modulating the effects of genetic and environmental factors on gene expression. Changes in methylation at the human leukocyte antigen gene (HLA-DRB1) have been previously associated with multiple sclerosis (MS) in both T lymphocytes and monocytes. This association is influenced by the well-established MS haplotype at this locus.
Objectives
To further characterise the cell-specific methylation profiles of MS by performing an epigenome-wide association study (EWAS) incorporating a statistical deconvolution of whole blood data
Methods
This was a case-control design involving subjects from the AusImmune Study. Specifically included were, 221 MS patients at first demyelination diagnosis and 468 population-based controls matched for age, sex and residential location. DNA methylation derived from whole blood was measured using Illumina EPIC arrays. EWAS analysis was performed using the ChAMP program. Cell deconvolution analysis was performed using the CellDMC function of the EpiDISH program . This method adjusts methylation levels by variation in blood cell proportions among subjects and can effectively estimate cell-specific methylation profiles without the need to do cell sorting. Gene set enrichment analysis (GSEA) was performed using the ToppGene program. All tests were assessed for statistical significance using a false discovery rate (FDR) of 0.05.
Results
The top differentially methylated region (DMR) was HLA-DRB1, which included both hypo and hyper methylation loci (PFDR<0.05). The underlying HLA-DRB1 haplotype was strongly associated with these DMRs. Deconvolution analyses showed that the HLA-DRB1 signal specifically originated from T cells and monocytes, which is consistent with previous findings. Interestingly, cell-specific GSEA revealed associations with pathways related to axonal guidance signalling, specifically in T cells, natural killer (NK) cells, and B cells. In particular, epigenetic variation in the Netrin-1 signalling pathway in both NK and B cells was associated with MS in this cohort (PFDR<0.05). Netrin‐1, is an axon guidance protein that reduces serum levels of pro-inflammatory mediators and stabilizes the blood-brain barrier limiting the entrance of immune cells into the central nervous system. These pathways were not detected in whole blood methylation analyses, highlighting the importance of the cellular deconvolution approach.
Conclusions
These results provide provisional evidence that epigenetic variation in axonal signalling pathways is associated with early-stage MS in a cell-dependent manner. If validated, these findings might help guide future efforts in epigenetic medicine for MS.